CN103848832A - Purification method of ertapenem sodium - Google Patents
Purification method of ertapenem sodium Download PDFInfo
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- CN103848832A CN103848832A CN201210497243.1A CN201210497243A CN103848832A CN 103848832 A CN103848832 A CN 103848832A CN 201210497243 A CN201210497243 A CN 201210497243A CN 103848832 A CN103848832 A CN 103848832A
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- solution
- sodium
- ertapenem
- ertapenem sodium
- aqueous solution
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- 229960002818 ertapenem sodium Drugs 0.000 title claims abstract description 105
- ZXNAQFZBWUNWJM-HRXMHBOMSA-M ertapenem sodium Chemical compound [Na+].O=C([C@H]1[NH2+]C[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C([O-])=O)=O)[C@H](O)C)NC1=CC=CC(C([O-])=O)=C1 ZXNAQFZBWUNWJM-HRXMHBOMSA-M 0.000 title claims abstract description 105
- 238000000746 purification Methods 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 88
- 239000007864 aqueous solution Substances 0.000 claims abstract description 40
- 239000002904 solvent Substances 0.000 claims abstract description 30
- 239000002994 raw material Substances 0.000 claims abstract description 27
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 239000011734 sodium Substances 0.000 claims abstract description 6
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 63
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 44
- 238000002425 crystallisation Methods 0.000 claims description 40
- 230000008025 crystallization Effects 0.000 claims description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000003929 acidic solution Substances 0.000 claims description 10
- 239000003637 basic solution Substances 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 229910001575 sodium mineral Inorganic materials 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003456 ion exchange resin Substances 0.000 claims description 5
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000003463 adsorbent Substances 0.000 claims description 3
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 229960001866 silicon dioxide Drugs 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 17
- 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 abstract description 2
- 239000000047 product Substances 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229960002770 ertapenem Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 101150116596 dhp-1 gene Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a purification method of ertapenem sodium. Specifically, the invention discloses a preparation method of low chroma ertapenem sodium. The method comprises the following steps: providing an ertapenem sodium raw material and an optional aqueous solution of inorganic alkali containing sodium; adjusting the pH value of the solution to 4.4-6.0, decolorizing, adjusting the pH value of the decolorized solution to 5.0-6.0, and adding a first solvent; and then adding a second solvent and crystallizing to obtain crystallized ertapenem sodium. The ertapenem sodium prepared by the method has stable chroma lighter than yellow green No.1, and is suitable for clinical application.
Description
Technical field
The invention belongs to chemical field.Particularly, the present invention relates to a kind of purification process of Ertapenem Sodium.
Background technology
Ertapenem Sodium (Ertapenem Sodium) is to be invented by AstraZeneca company of Britain, it is a kind of injection broad-spectrum long-acting carbapenem antibiotic, 2002 in U.S.'s Initial Public Offering, there is has a broad antifungal spectrum, to dehydropeptidase of kidney-1(DHP-1) stable, pharmacokinetic parameters is good, clinical therapeutic efficacy good, better tolerance, untoward reaction are few, long half time, the feature such as can be administered once for one day, be used for the treatment of clinically adult's moderate to the responsive microbial infection of severe, can obtain satisfactory effect to Community-acquired polyinfection.The structural formula of Ertapenem Sodium is as follows:
Ertapenem Sodium listing preparation commodity by name happy ten thousand it, clinical in intravenous infusion administration, must complete infusion in 6 hours at medicine dissolution.The color of medicine dissolution is colourless to faint yellow, and the color change occurring within the scope of this can not affect the curative effect of medicine.Once the colourity of raw material Ertapenem Sodium is defective, variable color rapidly after prepared preparation dissolves, has a strong impact on curative effect and even injures patient's life security.
In patent documentation WO2008062279, disclose two kinds of unformed Ertapenem Sodium preparation methods, the unformed material that these two kinds of crystallization protocol obtain is very unstable, and easily variable color and purity decline obviously, inapplicable suitability for industrialized production.
Patent documentation WO03026572 discloses Ertapenem Sodium A type crystallization and Type B crystallization and preparation method thereof.
Patent documentation CN200610004335 and CN02818431 disclose the preparation method of Ertapenem Sodium C type crystallization.
Patent documentation WO2009150630 discloses Ertapenem Sodium D type crystallization and preparation method thereof.
Patent documentation CN102558182 discloses Ertapenem Sodium E type crystallization and preparation method thereof.
Patent documentation WO2012038979 discloses another kind of new Ertapenem Sodium crystallization and preparation method thereof.
But, there is following shortcoming in the preparation method of Ertapenem Sodium A, B, C, the various crystal formations of D: when Ertapenem Sodium is carried out to crystallization, all require the concentration of Ertapenem Sodium crystallization solution more than 100mg/ml, due to the easily reason such as degraded and polymerization of Ertapenem Sodium, the operations such as conventional concentrated and sodium filter will cause a large amount of degradeds of product.Preparation method's shortcoming of Ertapenem Sodium crystal formation E is that crystal seed obtains difficulty.And, the colourity situation of crystallization products therefrom is not all described in above-mentioned open source literature, and excessive concentration during due to crystallization, the colourity of the Ertapenem Sodium of gained is all difficult to meet the requirements.
Therefore, be necessary to develop that a kind of method is simple, colourity is easily controlled, be applicable to the purification process of the Ertapenem Sodium of suitability for industrialized production, to ensure drug quality and the clinical effectiveness of Ertapenem Sodium preparation.
Summary of the invention
The object of this invention is to provide that a kind of method is simple, colourity is easily controlled, be applicable to the purification process of the Ertapenem Sodium of suitability for industrialized production.The Ertapenem Sodium colourity that the method makes is low and stable, is applicable to preparation and follow-up clinical application.
First aspect present invention provides a kind of purification process of Ertapenem Sodium, comprises step:
A) provide the aqueous solution that comprises Ertapenem Sodium raw material, the described aqueous solution optionally contains containing sodium mineral alkali;
B) behind pH to 4.4～6.0 of regulating step aqueous solution a), add discoloring agent to decolour, thereby obtain the solution through decolouring;
C) regulate aforementioned pH to 5.0～6.0 of solution through decolouring, add the first solvent;
D) in solution c) obtaining in step, add the second solvent, stir, crystallization, thus obtain the Ertapenem Sodium through crystallization.
In another preference, step b) in, pH to 4.6～5.8 of regulating step aqueous solution a) (more preferably 4.6～5.0); And/or step c) in, regulate aforementioned pH to 5.3～5.8 of solution through decolouring.
In another preference, the purity of described Ertapenem Sodium raw material is 85%-97%; And/or
The purity of the described Ertapenem Sodium through crystallization is 97%-99.99%.
In another preference, described Ertapenem Sodium raw material comprises: the crystallization of Ertapenem Sodium A type, the crystallization of Ertapenem Sodium Type B, the crystallization of Ertapenem Sodium C type, the crystallization of Ertapenem Sodium D type, the crystallization of Ertapenem Sodium E type, unformed Ertapenem Sodium or its combination; And/or described comprising containing sodium mineral alkali: sodium carbonate, sodium bicarbonate, sodium hydroxide or its combination.
In another preference, described is sodium bicarbonate or sodium carbonate containing sodium mineral alkali.
In another preference, in step a), described Ertapenem Sodium raw material and described mol ratio containing sodium mineral alkali are 1:1～1:4; And/or the mass ratio of described water and described Ertapenem Sodium raw material is 6:1～12:1.
In another preference, step a) in, the temperature of the described aqueous solution that comprises Ertapenem Sodium raw material is controlled to-5～20 DEG C; And/or step b) in, before the pH of regulating step aqueous solution a), also comprise step: the temperature of step aqueous solution a) is controlled to-2～10 DEG C; And/or step c) in, regulating aforementionedly before the pH of solution of decolouring, also comprise step: the temperature of the solution through decolouring is controlled to-2～10 DEG C; And/or in steps d) in, before adding the second solvent, also comprise step: the temperature of the solution that step c) is obtained is controlled at 0～-40 DEG C (preferably-10～-25 DEG C).
In another preference, step b) in, adopt the pH of acidic solution regulating step aqueous solution a), wherein, described acidic solution is selected from lower group: formic acid or its C
1-4organic Alcohol solution, acetic acid or its C
1-4organic Alcohol solution, propionic acid or its C
1-4organic Alcohol solution or hydrochloric acid or its C
1-4organic Alcohol solution; And/or
Step c) in, adopt basic solution to regulate the aforementioned pH of solution through decolouring, wherein, described basic solution is selected from lower group: the aqueous solution of sodium hydroxide or C
1-4the aqueous solution of Organic Alcohol solution, sodium bicarbonate or C
1-4the aqueous solution of Organic Alcohol solution, sodium carbonate or C
1-4the aqueous solution of Organic Alcohol solution, 2 ethyl hexanoic acid sodium or C
1-4organic Alcohol solution.
In another preference, the methanol solution that described acidic solution is formic acid or the methanol solution of acetic acid.
In another preference, described acidic solution is the C of the formic acid of 1～25mol/L (being preferably 3～10mol/L)
1-4the C of the acetic acid of Organic Alcohol solution, 1～25mol/L (being preferably 3～10mol/L)
1-4the C of the propionic acid of Organic Alcohol solution, 1～25mol/L (being preferably 3～10mol/L)
1-4the C of the hydrochloric acid of Organic Alcohol solution or 1～25mol/L (being preferably 3～10mol/L)
1-4organic Alcohol solution.
In another preference, the aqueous solution that described basic solution is sodium hydroxide.
In another preference, the volumetric molar concentration of described basic solution is 1～25mol/L; Preferably, be 3～10mol/L; More preferably, be 3～5mol/L.
In another preference, described discoloring agent comprises: gac, carclazyte, diatomite, silicon-dioxide, ion exchange resin or polymeric adsorbent; And/or
The first described solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride; And/or
The second described solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride.
In another preference, described discoloring agent is gac or ion exchange resin.
In another preference, the first described solvent is methyl alcohol.
In another preference, the second described solvent is n-propyl alcohol.
In another preference, step c) in, the first solvent and step a) in the ratio of volume of institute water be 0.5:1～3:1; And/or in steps d) in, the second solvent and step a) ratio of the volume of middle institute water are 0.5:1～3:1.
In another preference, in steps d) in, after crystallization, also comprise step: filter, and use organic solvent washing filter cake.
In another preference, described organic solvent is selected from lower group: acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methylene dichloride, methyl alcohol, ethanol, n-propyl alcohol, Virahol or its combination; Be preferably methyl alcohol, ethanol, acetone, methylene dichloride, tetrahydrofuran (THF).
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tire out and state no longer one by one at this.
Embodiment
The inventor is by long-term and deep research, be surprised to find that a kind of Ertapenem Sodium purification process, the method is decoloured to ertapenem raw material within the scope of a lower pH, then within the scope of the 2nd higher pH, carry out crystallization, obtained colourity low and stable, meet Ertapenem Sodium product that injectable drug requires, for the further clinical application of this class medicine open prospect.On this basis, contriver has completed the present invention.
The invention provides a kind of purification process of Ertapenem Sodium, the method can make the Ertapenem Sodium of low colourity and chroma stability.
Now the preferred purification process of the Ertapenem Sodium to invention illustrates as follows, but it comprises the following steps:
A) under certain temperature (as-5～20 DEG C, preferably 0～5 DEG C), by soluble in water Ertapenem Sodium raw material, thereby provide the aqueous solution that comprises Ertapenem Sodium raw material, the described aqueous solution optionally contains containing sodium mineral alkali;
Wherein, described Ertapenem Sodium raw material is the Ertapenem Sodium that purity is lower, and for example purity is the Ertapenem Sodium of 85%-97% (being preferably 90%-95%).The Ertapenem Sodium of the described existing any form of Ertapenem Sodium raw material, for example unformed Ertapenem Sodium, any one or the known crystal formation of multiple Ertapenem Sodium or both combinations.The known crystal formation of described ertapenem comprises: the crystallization of Ertapenem Sodium A type, the crystallization of Ertapenem Sodium Type B, the crystallization of Ertapenem Sodium C type, the crystallization of Ertapenem Sodium D type, the crystallization of Ertapenem Sodium E type etc.It is described that to comprise the water-soluble of Ertapenem Sodium raw material can be also with the aqueous solution containing Ertapenem Sodium after the ertapenem deprotection reaction of protecting group.For example document J.Org.Chem, 2005,70, the aqueous solution after the ertapenem deprotection reaction described in 7489 ~ 7487.
Described comprises containing sodium mineral alkali: sodium carbonate, sodium bicarbonate, sodium hydroxide etc.; Be preferably sodium bicarbonate or sodium carbonate.
B) temperature of step aqueous solution a) is controlled to certain temperature (as-2～10 DEG C), then with acidic solution by pH regulator to the pH of step aqueous solution a) (if pH is 4.4～6.0; Preferably, pH is 4.6～5.8 or 4.6～5.0) after, add discoloring agent to decolour, thereby obtain the solution through decolouring;
A described pH should not be too low, otherwise easily cause product yield to reduce; A described pH should not be too high, otherwise easily cause product decolorizing effect not good.Wherein, described acidic solution is selected from lower group: formic acid or its C
1-4organic Alcohol solution, acetic acid or its C
1-4organic Alcohol solution, propionic acid or its C
1-4organic Alcohol solution or hydrochloric acid or its C
1-4organic Alcohol solution.In another preference, the methanol solution that described acidic solution is formic acid or the methanol solution of acetic acid.In another preference, described acidic solution is the C of the formic acid of 1～25mol/L (being preferably 3～10mol/L)
1-4the C of the acetic acid of Organic Alcohol solution, 1～25mol/L (being preferably 3～10mol/L)
1-4the C of the propionic acid of Organic Alcohol solution, 1～25mol/L (being preferably 3～10mol/L)
1-4the C of the hydrochloric acid of Organic Alcohol solution or 1～25mol/L (being preferably 3～10mol/L)
1-4organic Alcohol solution.
Described discoloring agent comprises: gac, carclazyte, diatomite, silicon-dioxide, ion exchange resin or polymeric adsorbent.Preferably, described discoloring agent is gac or ion exchange resin.
After should be understood that described decolouring step, comprise that filtration step, the filtrate of collection are the solution through decolouring.
C) will be controlled at certain temperature (as-2～10 DEG C) through the temperature of solution of decolouring, then with basic solution by pH regulator to the two pH of the aforementioned solution through decolouring (if pH is 5.0～6.0; Preferably, pH is 5.3～5.8), then add the first solvent;
Described pH should not be too high or too low, otherwise cause crystallization yield to reduce or the crystal purity that obtains inadequate.Wherein, described basic solution is selected from lower group: the aqueous solution of the sodium hydroxide of any concentration or C
1-4the aqueous solution of the sodium bicarbonate of Organic Alcohol solution, any concentration or C
1-4the aqueous solution of the sodium carbonate of Organic Alcohol solution, any concentration or C
1-4the aqueous solution or the C of the 2 ethyl hexanoic acid sodium of Organic Alcohol solution, any concentration
1-4organic Alcohol solution.In another preference, the aqueous solution that described basic solution is sodium hydroxide.In another preference, the volumetric molar concentration of described basic solution is 1～25mol/L; Preferably, be 3～10mol/L; More preferably, be 3～5mol/L.
The first described solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride etc.; Be preferably methyl alcohol.
The first described solvent and step a) ratio of the volume of institute's water are 0.5:1～3:1.
D) solution temperature abovementioned steps being obtained is controlled at certain temperature (as 0～-40 DEG C; Preferably-10～-25 DEG C), then add the second solvent, stir, crystallization, thus obtain the Ertapenem Sodium through crystallization.
Wherein, the second described solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol, methylene dichloride etc.Be preferably n-propyl alcohol.
The second described solvent and step a) ratio of the volume of institute's water are 0.5:1～3:1.
In steps d) in, after crystallization, also comprise step: filter, and use organic solvent washing filter cake.Wherein, described organic solvent is selected from lower group: acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methylene dichloride, methyl alcohol, ethanol, n-propyl alcohol, Virahol or its combination; Be preferably methyl alcohol, ethanol, acetone, methylene dichloride, tetrahydrofuran (THF).
Compared with prior art, major advantage of the present invention is:
The invention provides a kind of purification process of Ertapenem Sodium.Described method combines the steps such as decolouring and crystallization, make the Ertapenem Sodium product that colourity meets medicinal requirements, this product or its preparation are mixed with after solution, within the long period (at least 6 hours), its colourity still meets medicinal requirements, thereby ensure quality and the security of medicine, be applicable to clinical application.
Below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
Ertapenem raw material according to document [Zhang Yifeng. synthetic [J] of carbapenem antibiotic ertapenem. China Medicine University's journal, 2007,38 (4): 305-310] method of report prepares.
Standard color solution is referring to 2005 editions two annex IX A first methods of Chinese Pharmacopoeia.
Embodiment 1 prepares low colourity Ertapenem Sodium sample 1
By 1.86g NaHCO
3be dissolved in 60ml distilled water; Be cooled to 0～5 DEG C, add Ertapenem Sodium raw material 10.0g(purity 95%), molten clear.0～5 DEG C of acetic acid with 3mol/L-methanol solution regulates pH approximately 4.8 (note the one pH); add 2g activated carbon decolorizing 30min; filtering gac under argon shield and ice-water bath, with the aqueous sodium hydroxide solution adjusting pH approximately 5.3 (note the 2nd pH) of 3mol/L.Add 100ml methyl alcohol, be cooled to-20～-15 DEG C, drip 50ml n-propyl alcohol, low rate mixing 40min, drip again 100ml n-propyl alcohol, drip complete stirring and crystallizing 30min, filter, with a small amount of methanol wash filter cake, drain solvent, collect solid, obtain Ertapenem Sodium sample 1 (7.4g, white solid), HPLC purity 99.2%.
Get this product 1g, add after 0.9%NaCl solution 10ml dissolving, with yellow No. 1 or No. 1 standard color solution comparison of yellow-green colour.Result shows: the colourity of sample 1 is shallower than yellow-green colour No. 1.
Embodiment 2 prepares low colourity Ertapenem Sodium sample 2
By 1.41g Na
2cO
3be dissolved in 90ml distilled water, be cooled to 0～5 DEG C, add Ertapenem Sodium raw material 10.0g(purity 95%), molten clear.0～5 DEG C of acetic acid with 5mol/L-methanol solution regulates pH approximately 4.6 (note the one pH); Add 2g resin (model HP-20) to stir 20min, under argon shield and ice-water bath, filter, with the aqueous sodium hydroxide solution adjusting pH approximately 5.6 (note the 2nd pH) of 5mol/L.Add 200ml methyl alcohol, be cooled to-20～-15 DEG C, drip 90ml n-propyl alcohol, low rate mixing 80min, drip again 250ml n-propyl alcohol, drip complete stirring and crystallizing 90min, filter, with a small amount of washing with acetone filter cake, drain solvent, collect solid, obtain Ertapenem Sodium sample 2 (7.0g, white solid), HPLC purity 98.7%.
Get this product 1g, add after 0.9%NaCl solution 10ml dissolving, with yellow No. 1 or No. 1 standard color solution comparison of yellow-green colour.Result shows: the colourity of sample 2 is shallower than yellow-green colour No. 1.
Embodiment 3 prepares low colourity Ertapenem Sodium sample 3
By 1.76g NaHCO
3be dissolved in 120ml distilled water; Be cooled to 0～5 DEG C, add Ertapenem Sodium raw material 10.0g(purity 95%), molten clear.0～5 DEG C of acetic acid with 7mol/L-methanol solution regulates pH approximately 5.0 (note the one pH); add 2g activated carbon decolorizing 20min; filtering gac under argon shield and ice-water bath, with the sodium bicarbonate aqueous solution adjusting pH approximately 5.4 (note the 2nd pH) of 10mol/L.Add 70ml methyl alcohol, be cooled to-10～-15 DEG C, drip 50ml n-propyl alcohol, low rate mixing 70min, then drip 30ml n-propyl alcohol, drip complete stirring and crystallizing 10min; Filter, with a small amount of washed with dichloromethane filter cake, drain solvent, collect solid, obtain Ertapenem Sodium sample 3 (6.5g, white solid), HPLC purity 98.4%.
Get this product 1g, add after 0.9%NaCl solution 10ml dissolving, with yellow No. 1 or No. 1 standard color solution comparison of yellow-green colour.Result shows: the colourity of sample 3 is shallower than yellow-green colour No. 1.
Embodiment 4 prepares low colourity Ertapenem Sodium sample 4
By Ertapenem Sodium raw material 10.0g(purity 95%) be dissolved in 80ml distilled water; be cooled to 5～10 DEG C; with acetic acid-methanol solution adjusting pH approximately 4.6 (note the one pH) of 10mol/L; add 5g resin (model HP-20) decolouring 5min; under argon shield and ice-water bath, filter, with the aqueous sodium carbonate adjusting pH approximately 5.4 (note the 2nd pH) of 5mol/L.Add 90ml methyl alcohol, be cooled to-20～-15 DEG C, drip 50ml n-propyl alcohol, low rate mixing 40min, drip again 50ml n-propyl alcohol, drip to finish and filter, with a small amount of tetrahydrofuran (THF) washing leaching cake, drain solvent, collect solid, obtain Ertapenem Sodium sample 4 (6.1g, white solid), HPLC purity 98.9%.
Get this product 1g, add after 0.9%NaCl solution 10ml dissolving, with yellow No. 1 or No. 1 standard color solution comparison of yellow-green colour.Result shows: the colourity of sample 4 is shallower than yellow-green colour No. 1.
Embodiment 5 prepares low colourity Ertapenem Sodium sample 5
According to document J.Org.Chem; 2005; 70; 7489 ~ 7487 disclosed methods; the aqueous solution (concentration is 140g/L, 100mL) of the Ertapenem Sodium that the ertapenem hydrogenation aftertreatment of protection is obtained; be cooled to 5～10 DEG C, with acetic acid-methanol solution adjusting pH approximately 4.9 (note the one pH) of 20mol/L.Add 5g activated carbon decolorizing 10min, under argon shield and ice-water bath, filter, with the sodium bicarbonate aqueous solution adjusting pH approximately 5.5 (note the 2nd pH) of 20mol/L.Add 120ml methyl alcohol, be cooled to-20～-15 DEG C, drip 90ml n-propyl alcohol, low rate mixing 40min, drip again 120ml n-propyl alcohol, drip to finish and filter, with a small amount of washing with alcohol filter cake, drain solvent, collect solid, obtain Ertapenem Sodium sample 5(7.7g, white solid), HPLC purity 98.0%.
Get this product 1g, add after 0.9%NaCl solution 10ml dissolving, with yellow standard color solution or the comparison of yellow-green colour standard color solution.Result shows: the colourity of sample 5 is shallower than yellow-green colour No. 1.
Comparative example 1
Preparation method can be with reference to the embodiment of CN02818431 1, makes Ertapenem Sodium reference substance 1 (85 grams), gets this product 1g, adds after 0.9%NaCl solution 10ml dissolving, with yellow standard color solution or the comparison of yellow-green colour standard color solution.Result shows: the colourity of reference substance 1 is about yellow No. 6.
Comparative example 2
Preparation method can be with reference to the embodiment of CN200510030660 1, make Ertapenem Sodium reference substance 2 (0.30g, yield 60%), get this product 1g, add after 0.9%NaCl solution 10ml dissolving, with yellow standard color solution or the comparison of yellow-green colour standard color solution.Result shows: the colourity of reference substance 1 is about yellow No. 7.
Comparative example 3-4
Preparation method is with embodiment 1, and difference is the pH described in employing table 1:
Table 1
| ? | The one pH | Product colourity | Yield |
| Comparative example 3 | 4.0 | Be shallower than yellow-green colour No. 1 | 10% |
| Comparative example 4 | 6.5 | Yellow No. 7 | 60% |
Result shows: when when decolouring, pH value is too high, product colourity very poor (far exceeding yellow-green colour No. 1), does not meet medicinal requirements; When decolouring, the too low product yield that causes of pH value is low, does not meet industrialized requirement.
Comparative example 5
First group: operation, with embodiment 1, repeats 10 times, products obtained therefrom is designated as batch 1-batches 10 successively.
Second group: proceed as follows, repeat 10 times, products obtained therefrom is designated as batch 11-batches 20 successively:
By 1.86g NaHCO
3be dissolved in 60ml distilled water; Be cooled to 0～5 DEG C, add Ertapenem Sodium raw material 10.0g(purity 95%), molten clear.0～5 DEG C of acetic acid with 3mol/L-methanol solution regulates pH approximately 5.5, adds 2g activated carbon decolorizing 30min, filtering gac under argon shield and ice-water bath.Add 100ml methyl alcohol, be cooled to-20～-15 DEG C, drip 50ml n-propyl alcohol, low rate mixing 40min, then drip 100ml n-propyl alcohol, and drip complete stirring and crystallizing 30min, filter, with a small amount of methanol wash filter cake, drain solvent, collect solid, obtain Ertapenem Sodium.
Get the product 1g of batch 1-20, add after 0.9%NaCl solution 10ml dissolving, with yellow No. 1 or No. 1 standard color solution comparison of yellow-green colour.Result is as shown in table 2.
Table 2
Result shows: adopt method of the present invention to process after Ertapenem Sodium raw material, the low and product chroma stability of each batch that makes of the Ertapenem Sodium colourity of gained, all meets pharmaceutical quality standard.
Show in sum: ertapenem purification process of the present invention, within the scope of a pH, decolour, in the second scope, carry out crystallization, can obtain the Ertapenem Sodium product that colourity is low and stable, be more suitable for clinical.
All documents of mentioning in the present invention are all quoted as a reference in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a purification process for Ertapenem Sodium, is characterized in that, comprises step:
A) provide the aqueous solution that comprises Ertapenem Sodium raw material, the described aqueous solution optionally contains containing sodium mineral alkali;
B) behind pH to 4.4～6.0 of regulating step aqueous solution a), add discoloring agent to decolour, thereby obtain the solution through decolouring;
C) regulate aforementioned pH to 5.0～6.0 of solution through decolouring, add the first solvent;
D) in solution c) obtaining in step, add the second solvent, stir, crystallization, thus obtain the Ertapenem Sodium through crystallization.
2. purification process as claimed in claim 1, is characterized in that,
Step b) in, pH to 4.6～5.8 of regulating step aqueous solution a) (more preferably 4.6～5.0); And/or
Step c) in, regulate aforementioned pH to 5.3～5.8 of solution through decolouring.
3. purification process as claimed in claim 1, is characterized in that,
The purity of described Ertapenem Sodium raw material is 85%-97%; And/or
The purity of the described Ertapenem Sodium through crystallization is 97%-99.99%.
4. purification process as claimed in claim 1, is characterized in that,
Described Ertapenem Sodium raw material comprises: the crystallization of Ertapenem Sodium A type, the crystallization of Ertapenem Sodium Type B, the crystallization of Ertapenem Sodium C type, the crystallization of Ertapenem Sodium D type, the crystallization of Ertapenem Sodium E type, unformed Ertapenem Sodium or its combination; And/or
Described comprises containing sodium mineral alkali: sodium carbonate, sodium bicarbonate, sodium hydroxide or its combination.
5. purification process as claimed in claim 1, is characterized in that, in step a),
Described Ertapenem Sodium raw material and described mol ratio containing sodium mineral alkali are 1:1～1:4; And/or
The mass ratio of described water and described Ertapenem Sodium raw material is 6:1～12:1.
6. purification process as claimed in claim 1, is characterized in that,
Step a) in, the temperature of the described aqueous solution that comprises Ertapenem Sodium raw material is controlled to-5～20 DEG C; And/or
Step b) in, before the pH of regulating step aqueous solution a), also comprise step: the temperature of step aqueous solution a) is controlled to-2～10 DEG C; And/or
Step c) in, regulating aforementionedly before the pH of solution of decolouring, also comprise step: the temperature of the solution through decolouring is controlled to-2～10 DEG C; And/or
In steps d) in, before adding the second solvent, also comprise step: the temperature of the solution that step c) is obtained is controlled at 0～-40 DEG C.
7. purification process as claimed in claim 1, is characterized in that,
Step b) in, adopt the pH of acidic solution regulating step aqueous solution a), wherein, described acidic solution is selected from lower group: formic acid or its C
1-4organic Alcohol solution, acetic acid or its C
1-4organic Alcohol solution, propionic acid or its C
1-4organic Alcohol solution or hydrochloric acid or its C
1-4organic Alcohol solution; And/or
Step c) in, adopt basic solution to regulate the aforementioned pH of solution through decolouring, wherein, described basic solution is selected from lower group: the aqueous solution of sodium hydroxide or C
1-4the aqueous solution of Organic Alcohol solution, sodium bicarbonate or C
1-4the aqueous solution of Organic Alcohol solution, sodium carbonate or C
1-4the aqueous solution of Organic Alcohol solution, 2 ethyl hexanoic acid sodium or C
1-4organic Alcohol solution.
8. purification process as claimed in claim 1, is characterized in that,
Described discoloring agent comprises: gac, carclazyte, diatomite, silicon-dioxide, ion exchange resin or polymeric adsorbent; And/or
The first described solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride; And/or
The second described solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol or methylene dichloride.
9. purification process as claimed in claim 1, is characterized in that,
Step c) in, the first solvent and step a) in the ratio of volume of institute water be 0.5:1～3:1; And/or
In steps d) in, the second solvent and step a) ratio of the volume of middle institute water are 0.5:1～3:1.
10. purification process as claimed in claim 1, is characterized in that, in steps d) in, after crystallization, also comprise step: filter, and use organic solvent washing filter cake.
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| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
| CN106749258A (en) * | 2015-11-24 | 2017-05-31 | 重庆圣华曦药业股份有限公司 | Method for purifying ertapenem sodium |
| CN113416193A (en) * | 2021-08-23 | 2021-09-21 | 凯莱英医药集团（天津）股份有限公司 | Novel ertapenem sodium crystal form and preparation method thereof |
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| CN102363617A (en) * | 2011-11-09 | 2012-02-29 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
| CN102690266A (en) * | 2011-09-02 | 2012-09-26 | 深圳市海滨制药有限公司 | Method for preparing ertapenem sodium |
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| WO2009150630A2 (en) * | 2008-06-11 | 2009-12-17 | Ranbaxy Laboratories Limited | Process for preparing a carbapenem antibiotic composition |
| CN102690266A (en) * | 2011-09-02 | 2012-09-26 | 深圳市海滨制药有限公司 | Method for preparing ertapenem sodium |
| CN102363617A (en) * | 2011-11-09 | 2012-02-29 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
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| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
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| CN113416193A (en) * | 2021-08-23 | 2021-09-21 | 凯莱英医药集团（天津）股份有限公司 | Novel ertapenem sodium crystal form and preparation method thereof |
| CN113416193B (en) * | 2021-08-23 | 2021-12-17 | 凯莱英医药集团（天津）股份有限公司 | New crystal form of ertapenem sodium and preparation method thereof |
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