CN102964355A - Preparation method of penicillin G sulfoxide - Google Patents
Preparation method of penicillin G sulfoxide Download PDFInfo
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- CN102964355A CN102964355A CN2012105478025A CN201210547802A CN102964355A CN 102964355 A CN102964355 A CN 102964355A CN 2012105478025 A CN2012105478025 A CN 2012105478025A CN 201210547802 A CN201210547802 A CN 201210547802A CN 102964355 A CN102964355 A CN 102964355A
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- Prior art keywords
- penicillin
- sulfoxide
- solution
- preparation
- concentration
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- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract description 30
- 239000000047 product Substances 0.000 claims abstract description 22
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012528 membrane Substances 0.000 claims abstract description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 11
- 239000000706 filtrate Substances 0.000 claims abstract description 11
- 238000001728 nano-filtration Methods 0.000 claims abstract description 10
- 229940056360 penicillin g Drugs 0.000 claims abstract description 10
- 238000000855 fermentation Methods 0.000 claims abstract description 9
- 230000004151 fermentation Effects 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 4
- 230000001105 regulatory effect Effects 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 26
- 230000003647 oxidation Effects 0.000 claims description 21
- 238000007254 oxidation reaction Methods 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 16
- 229930182555 Penicillin Natural products 0.000 claims description 10
- 229940049954 penicillin Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 239000000919 ceramic Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 abstract description 20
- 238000001914 filtration Methods 0.000 abstract description 11
- 238000005406 washing Methods 0.000 abstract description 7
- 238000000605 extraction Methods 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 abstract 1
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- 239000012535 impurity Substances 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003987 high-resolution gas chromatography Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
The invention discloses a novel method for preparing penicillin G sulfoxide, which comprises the following steps: a, selecting a 60000-120000 mu/g penicillin G fermentation solution, and dropwisely adding peroxyacetic acid to obtain a solution I; b, filtering the solution I to obtain a filtrate, and concentrating the filtrate through a nanofiltration membrane of which the molecular weight cut-off is 200-800Da, thus obtaining a concentrated solution; c, regulating the pH value of the concentrated solution with sulfuric acid, and filtering to obtain a penicillin G sulfoxide crude product; and d, dissolving the penicillin G sulfoxide crude product in a methanol water solution, recrystallizing, then cooling to 0-10 DEG C, filtering, washing the obtained crystals with methanol, swabbing off, and performing microwave drying on the obtained product to obtain the penicillin G sulfoxide. According to the invention, the method is simple, the process period is short, and extraction treatment can be performed without using a large amount of organic solvent. Thus, the method disclosed by the invention is low in cost and environment-friendly.
Description
Technical field
The invention belongs to chemical engineering crystallization technique field, be specifically related to a kind of penicillin G sulfoxide preparation method.
Background technology
Penicillin sulfoxide is by penicillin very important intermediate in the cynnematin conversion process.In the traditional processing technology flow process, penicillin G sulfoxide generally is to obtain take the penicillin G Industrial Salt as the raw material oxidation: cosmocillin obtains penicillin G sulfoxide through oxidation → crystallization → filtration → washing → drying and other steps, and the acquisition of cosmocillin is again through filtration → extraction → extracting → processes such as crystallization, so loaded down with trivial details from the whole Production Flow Chart complexity of penicillin fermentation liquid → penicillin G sulfoxide, and used a large amount of solvents to extract in this process, the power working cost is high, wastewater discharge is large, production cost is high.At present, people are trying to explore a kind of method for preparing penicillin G sulfoxide of simplifying.
Disclose a kind of method that directly prepares penicillin sulfoxide with penicillin fermentation liquid among the Chinese patent application CN2010105029756: penicillin fermentation liquid or penicillin salt solution add esters solvent makes it to change into penicillinic acid, then the penicillinic acid in the organic phase is added oxygenant and carry out oxidizing and crystallizing, from organic phase, extract the preparation penicillin sulfoxide.Though it is basic raw material that the method has penicillin fermentation liquid, its related technological process is still in fact penicillin is changed into the penicillinic acid intermediate, prepares penicillin sulfoxide with the oxidation of penicillinic acid intermediate again.
Summary of the invention
Purpose of the present invention just provides a kind of new method for preparing penicillin G sulfoxide, in the hope of simplifying technique, reducing cost, reduces discharge of wastewater, improves the environmental friendliness degree.
For achieving the above object, the method for preparing penicillin G sulfoxide provided by the present invention may further comprise the steps:
A. get the penicillin G fermented liquid of concentration 60000 ~ 120000 μ/g, under 0 ~ 8 ℃ of condition of temperature, drip mass volume ratio concentration and be 20 ~ 38% Peracetic Acid to the oxidation terminal point, get the solution I;
B. the solution I is got filtrate through 50 ~ 200nm ceramic membrane filter, gained filtrate is that the FW=100-500 nanofiltration membrane concentrates to get concentrated solution through molecular weight cut-off;
C. described concentrated solution is regulated PH to 1 ~ 1.5 with sulfuric acid, filters, and gets the penicillin G sulfoxide crude product;
D. described penicillin G sulfoxide crude product is dissolved in 9 ~ 80% methanol aqueous solutions, and then recrystallization under 40 ~ 48 ℃ of temperature condition is cooled to 0 ~ 10 ℃, filter, the gained crystal with methanol wash, drain, products therefrom microwave drying namely gets penicillin G sulfoxide.
9 ~ 80% methanol solutions of the present invention refer to contain methyl alcohol 9-80ml in the 100ml solution, and surplus is water.
In order further to improve the product comprehensive income, penicillin fermentation liquid preferred 60000 ~ 120000 μ/g that tires among the step a; The temperature of penicillin fermentation liquid is preferred 0 ~ 5 ℃ among the step a; The mass volume ratio of Peracetic Acid described in step a concentration preferred 29 ~ 33%; The preferred FW=200 of the molecular weight cut-off of nanofiltration membrane described in the step a ~ 300.
Optimum condition is during microwave drying: microwave frequency 915～2450MHZ, 10～20 minutes time of drying, the water capacity of wet product is controlled at 4%～8%.
The present invention prepares penicillin G sulfoxide with the direct oxidation of penicillin G fermented liquid, filtration, crystallization, recrystallization, and its method is simple, and process cycle is short, and need not adopt a large amount of organic solvents to carry out extraction process.Therefore cost is low, environmental friendliness.
Adopt method provided by the present invention to prepare penicillin G sulfoxide, also have the content height, the advantage that purity is good.
The penicillin G sulfoxide crystal that obtains through the inventive method is through spectrophotometer, high performance liquid chromatography, high resolution gas chromatography analysis, detection:
Its content (HPLC):＞99.8%;
Purity (HPLC):＞99.5%;
Moisture (KF) :≤0.1%;
425nm light absorption value :≤0.02;
Solvent is residual :≤0.1%.
Embodiment
Embodiment 1:
(concentration: 90000 μ/g), cryosel is bathed and is cooled to 0 ~ 5 ℃ to add 1000ml penicillin G fermented liquid in the 2000ml there-necked flask.Under the rapid stirring, dripping mass volume ratio concentration is that 30% Peracetic Acid stops oxidation (detecting the oxidation terminal point with potassium iodide starch test paper) to the oxidation terminal point, gets the solution I.The solution I leaches solid impurity through the 100nm ceramic membrane filter, suitable quantity of water washing impurity, filtration.Filtrate is concentrated with molecular weight cut-off FW=500 nanofiltration membrane.Concentrated solution is adjusted to filter under PH=1～1.5,0 ~ 20 ℃ with sulfuric acid and gets penicillin G sulfoxide crude product (wet product).This penicillin G sulfoxide crude product (wet product) is put in 60% methanol solution 40～48 ℃ of lower recrystallizations.Be cooled to 0～10 ℃, filter.With 0 ℃ of methanol wash, drain.Product is dry in microwave.Get penicillin G sulfoxide 42.5g, yield is 80%.
Embodiment 2:
(concentration: 95000 μ/g), cryosel is bathed and is cooled to 0 ~ 5 ℃ to add 1000ml penicillin G fermented liquid in the 2000ml there-necked flask.Under the rapid stirring, dripping mass volume ratio concentration is that 33% Peracetic Acid stops oxidation (detecting the oxidation terminal point with potassium iodide starch test paper) to the oxidation terminal point, gets the solution I.The solution I leaches solid impurity through the 50nm ceramic membrane filter, suitable quantity of water washing impurity, filtration.Filtrate is concentrated with molecular weight cut-off FW=200 nanofiltration membrane.Concentrated solution is adjusted to filter under PH=1～1.5,0 ~ 20 ℃ with sulfuric acid and gets penicillin G sulfoxide crude product (wet product).This penicillin G sulfoxide crude product (wet product) is put in 80% methanol aqueous solution 40～48 ℃ of lower recrystallizations.Be cooled to 0～10 ℃, filter.With 0 ℃ of methanol wash, drain.Product is dry in microwave.The microwave drying condition is: microwave frequency 915～2450MHZ, 10～20 minutes time of drying, the water capacity of wet product is controlled at 4%～8%.Get penicillin G sulfoxide 47.2g after the microwave drying, yield is 85.4%.
Embodiment 3:
(concentration: 60000 μ/g), cryosel is bathed and is cooled to 0 ~ 8 ℃ to add 1000ml penicillin G fermented liquid in the 2000ml there-necked flask.Under the rapid stirring, dripping mass volume ratio concentration is that 28% Peracetic Acid stops oxidation (detecting the oxidation terminal point with potassium iodide starch test paper) to the oxidation terminal point, gets the solution I.The solution I leaches solid impurity through 200 μ m ceramic membrane filters, suitable quantity of water washing impurity, filtration.Filtrate is concentrated with molecular weight cut-off FW=800 nanofiltration membrane.Concentrated solution is adjusted to filter under PH=1～1.5,0 ~ 20 ℃ with sulfuric acid and gets penicillin G sulfoxide crude product (wet product).This penicillin G sulfoxide crude product (wet product) is put in 9% methanol aqueous solution 35～40 ℃ of lower recrystallizations.Be cooled to 0～10 ℃, filter.With 0 ℃ of methanol wash, drain.Product is dry in microwave.Get penicillin G sulfoxide 27.7g, yield is 78%.
Embodiment 4:
(concentration: 120000 μ/g), cryosel is bathed and is cooled to 0 ~ 8 ℃ to add 1000ml penicillin G fermented liquid in the 2000ml there-necked flask.Under the rapid stirring, dripping mass volume ratio concentration is that 20% Peracetic Acid stops oxidation (detecting the oxidation terminal point with potassium iodide starch test paper) to the oxidation terminal point, gets the solution I.The solution I leaches solid impurity through the 200nm ceramic membrane filter, suitable quantity of water washing impurity, filtration.Filtrate is concentrated with molecular weight cut-off FW=200-300 molecular weight nanofiltration membrane.Concentrated solution is adjusted to filter under PH=1～1.5,0 ~ 20 ℃ with sulfuric acid and gets penicillin G sulfoxide crude product (wet product).This penicillin G sulfoxide crude product (wet product) is put in 9% methanol aqueous solution 35～40 ℃ of lower recrystallizations.Be cooled to 0～10 ℃, filter.With 0 ℃ of methanol wash, drain.Product is dry in microwave.Get penicillin G sulfoxide 54.6g, yield is 76.9%.
Embodiment 5:
(concentration: 90000 μ/g), cryosel is bathed and is cooled to 0 ~ 5 ℃ to add 1000ml penicillin G fermented liquid in the 2000ml there-necked flask.Under the rapid stirring, dripping mass volume ratio concentration is that 38% Peracetic Acid stops oxidation (detecting the oxidation terminal point with potassium iodide starch test paper) to the oxidation terminal point, gets the solution I.The solution I leaches solid impurity through the 150nm ceramic membrane filter, suitable quantity of water washing impurity, filtration.Filtrate is concentrated with molecular weight cut-off FW=200 molecular weight nanofiltration membrane.Concentrated solution is adjusted to filter under PH=1～1.5,0 ~ 20 ℃ with sulfuric acid and gets penicillin G sulfoxide crude product (wet product).This penicillin G sulfoxide crude product (wet product) is put in 45% methanol aqueous solution 35～45 ℃ of lower recrystallizations.Be cooled to 0～10 ℃, filter.With 0 ℃ of methanol wash, drain.Product is dry in microwave.Get penicillin G sulfoxide 42.8g, yield is 80.5%.
Claims (6)
1. penicillin G sulfoxide preparation method is characterized in that it may further comprise the steps:
A. get the penicillin G fermented liquid of concentration 60000 ~ 120000 μ/g, under 0 ~ 8 ℃ of condition of temperature, drip mass volume ratio concentration and be 20 ~ 38% Peracetic Acid to the oxidation terminal point, get the solution I;
B. the solution I is got filtrate through 50 ~ 200nm ceramic membrane filter, gained filtrate is the concentrated concentrated solution that to get of nanofiltration membrane of FW=100 ~ 500 through molecular weight cut-off;
C. described concentrated solution is regulated PH to 1 ~ 1.5 with sulfuric acid, filters, and gets the penicillin G sulfoxide crude product;
D. to be dissolved in volume by volume concentration be in 9 ~ 80% methanol aqueous solutions to described penicillin G sulfoxide crude product, and then recrystallization under 40 ~ 48 ℃ of temperature condition is cooled to 0 ~ 10 ℃, filter, the gained crystal with methanol wash, drain, products therefrom microwave drying namely gets penicillin G sulfoxide.
2. penicillin G sulfoxide preparation method according to claim 1 is characterized in that among the step a that it is 60000 ~ 120000 μ/g that penicillin fermentation liquid is tired.
3. penicillin G sulfoxide preparation method according to claim 1, the temperature that it is characterized in that penicillin fermentation liquid among the step a is 0 ~ 5 ℃.
4. penicillin G sulfoxide preparation method according to claim 1 is characterized in that the concentration of Peracetic Acid mass volume ratio described in the step a is 29 ~ 33%.
5. penicillin G sulfoxide preparation method according to claim 1 is characterized in that nanofiltration membrane molecular weight cut-off described in the step a is FW=200 ~ 300.
6. penicillin G sulfoxide preparation method according to claim 1 is characterized in that crossing described in the steps d microwave drying, its microwave frequency 915 ~ 2450MHZ, and 10 ~ 20 minutes time of drying, the water capacity of wet product is controlled at 4% ~ 8%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210547802.5A CN102964355B (en) | 2012-12-17 | 2012-12-17 | Preparation method of penicillin G sulfoxide |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210547802.5A CN102964355B (en) | 2012-12-17 | 2012-12-17 | Preparation method of penicillin G sulfoxide |
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| CN102964355B CN102964355B (en) | 2015-07-01 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693747A (en) * | 2016-03-07 | 2016-06-22 | 内蒙古常盛制药有限公司 | Solvent-free washing and drying technology for 6-APA (6-aminopenicillanic acid) |
| CN111233892A (en) * | 2018-11-28 | 2020-06-05 | 江苏悦新药业有限公司 | Method for synthesizing penicillin G sulfoxide by using continuous flow reactor |
| CN112358489A (en) * | 2020-11-09 | 2021-02-12 | 华北制药股份有限公司 | Production method of industrial penicillin sulfoxide product |
Citations (5)
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|---|---|---|---|---|
| US4230620A (en) * | 1979-03-26 | 1980-10-28 | Eli Lilly And Company | Process for preparing penicillin sulfoxides |
| CN1201795A (en) * | 1998-05-22 | 1998-12-16 | 范伟光 | Preparation of 7-amino-deacetylated cefa-alkylation acid |
| CN1332169A (en) * | 2000-07-10 | 2002-01-23 | 中国科学院化工冶金研究所 | Method of eliminating water and other impurities from coarse penicillin G sulfoxide |
| CN101735246A (en) * | 2008-11-05 | 2010-06-16 | 杨石 | Method for preparing cephalosporin intermediate 7-ADCA |
| CN101974017A (en) * | 2010-10-11 | 2011-02-16 | 天津大学 | Method for preparing penicillin-G-1-(S)-oxide |
-
2012
- 2012-12-17 CN CN201210547802.5A patent/CN102964355B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4230620A (en) * | 1979-03-26 | 1980-10-28 | Eli Lilly And Company | Process for preparing penicillin sulfoxides |
| CN1201795A (en) * | 1998-05-22 | 1998-12-16 | 范伟光 | Preparation of 7-amino-deacetylated cefa-alkylation acid |
| CN1332169A (en) * | 2000-07-10 | 2002-01-23 | 中国科学院化工冶金研究所 | Method of eliminating water and other impurities from coarse penicillin G sulfoxide |
| CN101735246A (en) * | 2008-11-05 | 2010-06-16 | 杨石 | Method for preparing cephalosporin intermediate 7-ADCA |
| CN101974017A (en) * | 2010-10-11 | 2011-02-16 | 天津大学 | Method for preparing penicillin-G-1-(S)-oxide |
Non-Patent Citations (3)
| Title |
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| 史兰香 等: "青霉素制备青霉素亚砜", 《精细化工》 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693747A (en) * | 2016-03-07 | 2016-06-22 | 内蒙古常盛制药有限公司 | Solvent-free washing and drying technology for 6-APA (6-aminopenicillanic acid) |
| CN105693747B (en) * | 2016-03-07 | 2018-02-06 | 内蒙古常盛制药有限公司 | A kind of 6 APA is without the dry technology of solvent washing |
| CN111233892A (en) * | 2018-11-28 | 2020-06-05 | 江苏悦新药业有限公司 | Method for synthesizing penicillin G sulfoxide by using continuous flow reactor |
| CN111233892B (en) * | 2018-11-28 | 2022-10-14 | 江苏悦新药业有限公司 | Method for synthesizing penicillin G sulfoxide by using continuous flow reactor |
| CN112358489A (en) * | 2020-11-09 | 2021-02-12 | 华北制药股份有限公司 | Production method of industrial penicillin sulfoxide product |
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Inventor after: Wei Qingjie Inventor after: Zhang Miaojing Inventor after: Zheng Baoli Inventor after: Gao Junyan Inventor after: Feng Lifeng Inventor after: Yan Feng Inventor after: Wang Liqiang Inventor after: Zhang Wei Inventor after: Yin Keke Inventor after: Zhao Wei Inventor after: Yang Liting Inventor after: Duan Zhigang Inventor after: Ma Like Inventor after: Wu Xiang Inventor after: Chen Hao Inventor after: Liu Hailian Inventor after: Liu Dong Inventor after: Zhang Suoqing Inventor after: Mi Zhenrui Inventor after: Liu Mingru Inventor after: Fu Chengming Inventor after: Wang Dong Inventor after: Yang Fan Inventor before: Wei Qingjie Inventor before: Zhang Miaojing Inventor before: Zheng Baoli Inventor before: Gao Junyan Inventor before: Feng Lifeng Inventor before: Duan Zhigang Inventor before: Liu Dong Inventor before: Zhang Suoqing Inventor before: Mi Zhenrui Inventor before: Liu Mingru Inventor before: Fu Chengming Inventor before: Wang Dong Inventor before: Yang Fan |
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Free format text: CORRECT: INVENTOR; FROM: WEI QINGJIE DUAN ZHIGANG LIU DONG ZHANG SUOQING MI ZHENRUI LIU MINGRU FU CHENGMING WANG DONG YANG FAN ZHANG MIAOJING ZHENG BAOLI GAO JUNYAN FENG LIFENG TO: WEI QINGJIE DUAN ZHIGANG LIU DONG ZHANG SUOQING MI ZHENRUI LIU MINGRU FU CHENGMING WANG DONG YANG FAN ZHANG MIAOJING ZHENG BAOLI GAO JUNYAN FENG LIFENG YAN FENG WANG LIQIANG ZHANG WEI YIN KEKE ZHAO WEI YANG LITING MA LIKE WU XIANG CHEN HAO LIU HAILIAN |
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Effective date of registration: 20190211 Address after: 050000 No. 388 Heping East Road, Shijiazhuang City, Hebei Province Patentee after: Huabei Pharmaceutical Co., Ltd. Address before: 052165 No. 98 Hainan Road, Liangcun Economic and Technological Development Zone, Shijiazhuang City, Hebei Province Patentee before: NCPC Hebei Huamin Pharma Co., Ltd. |