CN117534683A - Preparation method of clavulanate potassium - Google Patents
Preparation method of clavulanate potassium Download PDFInfo
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- CN117534683A CN117534683A CN202311498562.9A CN202311498562A CN117534683A CN 117534683 A CN117534683 A CN 117534683A CN 202311498562 A CN202311498562 A CN 202311498562A CN 117534683 A CN117534683 A CN 117534683A
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- China
- Prior art keywords
- potassium
- clavulanate
- resin
- potassium clavulanate
- clavulanic acid
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- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 title claims abstract description 138
- 229940038649 clavulanate potassium Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims abstract description 100
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims abstract description 99
- 229960003324 clavulanic acid Drugs 0.000 claims abstract description 94
- 239000011347 resin Substances 0.000 claims abstract description 78
- 229920005989 resin Polymers 0.000 claims abstract description 78
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 57
- 239000000243 solution Substances 0.000 claims abstract description 52
- 239000007864 aqueous solution Substances 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 34
- 238000001179 sorption measurement Methods 0.000 claims abstract description 27
- 239000012528 membrane Substances 0.000 claims abstract description 22
- 238000001223 reverse osmosis Methods 0.000 claims abstract description 14
- 239000012141 concentrate Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000013078 crystal Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical group OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 25
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 20
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 19
- 239000011736 potassium bicarbonate Substances 0.000 claims description 19
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000007791 liquid phase Substances 0.000 claims description 15
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 14
- 238000003795 desorption Methods 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 11
- 238000004108 freeze drying Methods 0.000 claims description 10
- 230000004913 activation Effects 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 238000002834 transmittance Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 235000011181 potassium carbonates Nutrition 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229940090805 clavulanate Drugs 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 238000011010 flushing procedure Methods 0.000 claims description 4
- 230000009466 transformation Effects 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 3
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 claims description 2
- 239000004952 Polyamide Substances 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims description 2
- 238000004042 decolorization Methods 0.000 claims description 2
- MYTMXVHNEWBFAL-UHFFFAOYSA-L dipotassium;carbonate;hydrate Chemical compound O.[K+].[K+].[O-]C([O-])=O MYTMXVHNEWBFAL-UHFFFAOYSA-L 0.000 claims description 2
- 239000004745 nonwoven fabric Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229920002492 poly(sulfone) Polymers 0.000 claims description 2
- 229920002647 polyamide Polymers 0.000 claims description 2
- 229920000728 polyester Polymers 0.000 claims description 2
- -1 amine salt Chemical class 0.000 abstract description 10
- 238000000855 fermentation Methods 0.000 abstract description 10
- 230000004151 fermentation Effects 0.000 abstract description 10
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 description 24
- 238000011068 loading method Methods 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 239000003463 adsorbent Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000187433 Streptomyces clavuligerus Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 229960002793 amoxicillin sodium Drugs 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 125000005587 carbonate group Chemical group 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000012792 lyophilization process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229960004659 ticarcillin Drugs 0.000 description 2
- ZBBCUBMBMZNEME-QBGWIPKPSA-L ticarcillin disodium Chemical compound [Na+].[Na+].C=1([C@@H](C([O-])=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)C=CSC=1 ZBBCUBMBMZNEME-QBGWIPKPSA-L 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 238000005092 sublimation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/02—Preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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
- C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 unsubstituted in position 6
- C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring 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 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
- C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
- C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmacy, and relates to a preparation method of potassium clavulanate. The preparation method comprises the following steps: acidifying aqueous solution of clavulanic acid, adsorbing clavulanic acid on the resin by nonpolar macroporous adsorption resin, and resolving by using resolving agent to obtain clavulanic acid potassium resolving solution; the potassium clavulanate analytic solution is decolorized by anion exchange resin and concentrated by a high-pressure reverse osmosis membrane to obtain potassium clavulanate concentrated solution; the clavulanate potassium concentrate is freeze-dried to obtain clavulanate potassium crystal. According to the preparation method disclosed by the invention, clavulanic acid is extracted from fermentation liquor without an amine salt intermediate and is directly converted into clavulanate potassium, the process design is innovative, the operation is simple and convenient, the energy consumption is low, and the obtained clavulanate potassium product has high and stable quality and meets the pharmacopoeia standard.
Description
Technical Field
The invention belongs to the technical field of pharmacy, relates to a preparation method of clavulanate potassium, and in particular relates to a method for extracting clavulanic acid from clavulanic acid fermentation liquor and converting the clavulanic acid into clavulanate potassium.
Background
Potassium clavulanate is a beta-lactamase inhibitor, and can inhibit the decomposition of bacteria to beta-lactam antibiotics, and restore the antibacterial activity of penicillin and cephalosporin antibiotics to drug-resistant bacteria producing beta-lactamase. The compound amoxicillin or ticarcillin sodium can be used by compounding, so that the minimum antibacterial concentration of the compound amoxicillin or ticarcillin sodium can be obviously reduced. Compared with other beta-lactamase inhibitors, clavulanate potassium has wider and stronger inhibition effect, so that the clavulanate potassium is widely applied clinically, and the market sales in recent years are always in an ascending state.
At present, the industrial preparation process of the clavulanate mainly comprises the following steps: clavulanic acid is first produced by fermentation with streptomyces clavuligerus, then clavulanic acid is converted into an amine salt intermediate of clavulanic acid through a series of purification, concentration and crystallization processes, and finally the amine salt intermediate is dissolved, converted, and after decolorization and crystallization, the amine salt intermediate of clavulanic acid is converted into potassium clavulanate. The amine salt intermediate is mainly clavulanic acid tert-butylamine. The industrial preparation method can obtain a high-purity clavulanate potassium crystal product, but in the production process, toxic amine salt intermediates and a large amount of organic solvents are used, and the substances are difficult to completely remove from wastewater, so that the environment is polluted, and meanwhile, the production cost is increased; in addition, the existing preparation method has the advantages of more process steps, high energy consumption and low process yield, thereby leading to high production cost of the potassium clavulanate. Based on the defects of the existing preparation process of the clavulanate potassium, scholars at home and abroad develop a one-step crystallization process for directly converting the clavulanic acid into the clavulanate potassium without an amine salt intermediate, the method lacks the intermediate crystallization and purification process of the clavulanate amine salt, the process steps are simplified, the product yield is improved, but the formed clavulanate potassium product reported by the current literature or patent has low purity, poor quality, very instability and very easy inactivation. Therefore, how to effectively extract and prepare high-quality potassium clavulanate from biological fermentation liquor in high yield has important practical significance, and needs to be continuously researched and improved.
Disclosure of Invention
Technical problem
The present invention has been designed to solve the above-mentioned problems of the prior art, and an object of the present invention is to provide a method for preparing potassium clavulanate, which extracts clavulanate from a fermentation broth without an amine salt intermediate and directly converts it into potassium clavulanate, which has innovative process design, simple operation, low energy consumption, and high and stable quality of the obtained potassium clavulanate product.
Technical proposal
In order to achieve the above purpose of the present invention, the present invention adopts the following technical scheme: removing mycelium and other solids from the clavulanic acid fermentation broth by methods known in the art, and treating with an ultrafiltration membrane to obtain a clarified aqueous clavulanic acid solution; then adjusting the pH of the clavulanic acid aqueous solution to be acidic, and using macroporous adsorption resin to specifically adsorb the clavulanic acid from the clavulanic acid aqueous solution, wherein other impurities which are not adsorbed by the resin are separated and removed; then resolving clavulanic acid adsorbed on the resin by using a resolving agent and converting the clavulanic acid into potassium salt, and decolorizing the clavulanic acid potassium salt aqueous solution by using an anion exchange resin (converted into a hydrogen carbonate type or a carbonic acid type) to obtain a purified clavulanic acid potassium salt aqueous solution; and finally, concentrating the potassium clavulanate aqueous solution by using a high-pressure reverse osmosis membrane, and freeze-drying the obtained potassium clavulanate concentrated solution to obtain the potassium clavulanate with the product quality meeting the standard.
According to the present invention, the preparation method of potassium clavulanate provided by the present invention comprises the following steps:
(1) Adsorption, resolution and conversion of clavulanic acid
Acidizing an aqueous solution of clavulanic acid, adsorbing the clavulanic acid on the resin through nonpolar macroporous adsorption resin, washing the resin by using purified water, and then resolving the clavulanic acid adsorbed on the resin by using a resolving agent to convert the clavulanic acid into potassium clavulanate to obtain potassium clavulanate resolving solution;
wherein the desorbent is selected from the group consisting of aqueous potassium carbonate and aqueous potassium bicarbonate;
(2) Decoloring and concentrating the potassium clavulanate analytic solution
Passing the potassium clavulanate analytic solution obtained in the step (1) through bicarbonate anion exchange resin or carbonic acid anion exchange resin to obtain decolorized potassium clavulanate aqueous solution; concentrating the decolorized potassium clavulanate aqueous solution through a high-pressure reverse osmosis membrane to obtain potassium clavulanate concentrated solution;
wherein the carbonic acid type anion exchange resin is changed into carbonic acid type anion exchange resin through alkali activation and potassium bicarbonate water solution treatment, and the carbonic acid type anion exchange resin is changed into carbonic acid type anion exchange resin through alkali activation and potassium carbonate water solution treatment;
(3) Preparation of Potassium clavulanate
And (3) freeze-drying the potassium clavulanate concentrate obtained in the step (2) to obtain potassium clavulanate crystals.
Advantageous effects
In the invention, the nonpolar macroporous adsorption resin is creatively used to successfully realize the specific adsorption of clavulanic acid from the aqueous solution of clavulanic acid, and a large amount of pigments and impurities are not adsorbed on the resin, thus achieving the purpose of separating and purifying clavulanic acid; then, the clavulanic acid adsorbed on the resin is resolved by adopting a proper resolving agent and is synchronously converted into potassium clavulanate, thereby achieving the purpose of converting into salt. The method combines clavulanic acid purification and conversion, not only improves the production efficiency, but also abandons a large amount of organic solvents used in the traditional extraction process. In addition, the invention creatively applies the high-pressure reverse osmosis membrane to realize high-power concentration of the potassium clavulanate aqueous solution under the low-temperature condition, thereby greatly reducing the production cost while improving the product quality. The invention adopts the freeze-drying technology optimized by the system to freeze-dry the potassium clavulanate concentrate, and the finally obtained potassium clavulanate product can meet the quality standard in terms of quality parameters such as content, impurities and the like.
The invention is more suitable for popularization and application in industrial production compared with the prior art by combining the advantages.
Detailed Description
Hereinafter, the preparation method of potassium clavulanate according to the present invention will be described in more detail to aid in understanding the present invention.
According to one embodiment of the present invention, in the method for producing potassium clavulanate according to the present invention, in the adsorption, resolution and conversion of clavulanic acid in the step (1), the aqueous solution of clavulanic acid is acidified, and then the clavulanic acid is adsorbed on the resin through a nonpolar macroporous adsorption resin, and then the resin is washed with purified water, and then the clavulanic acid adsorbed on the resin is resolved using a resolving agent and converted into potassium clavulanate, to obtain a potassium clavulanate resolving solution.
In the art, clavulanic acid fermentation broth is generally produced by fermentation with streptomyces clavuligerus, mycelium and other solids in the fermentation broth are generally removed by filtration with a ceramic membrane, and soluble heteroproteins and pigments in the fermentation broth are then removed by ultrafiltration with an ultrafiltration membrane, so as to obtain a clarified clavulanic acid solution, wherein the concentration of clavulanic acid is generally 1.0-2.0 mg/mL, and the pH is generally 5.0-6.0. For example, ceramic membranes with pore diameters of 50-100 nanometers and ultrafiltration membranes with molecular weight cut-off of 5 KD-10 KD can be selected for use in the process.
The aqueous solution of clavulanic acid may be acidified with acids known in the art, for example sulfuric acid having a concentration of 10% to 15% (v/v) or hydrochloric acid having a concentration of 20% to 30% (v/v), and the aqueous solution of clavulanic acid after the acidification preferably has a pH of 0.5 to 1.0. Under the pH condition, the clavulanic acid in the aqueous solution exists in a molecular form and can be specifically adsorbed on nonpolar macroporous adsorption resin, and other impurities exist in an ionic form in the pH range, so that the impurities are not adsorbed by the resin, and the purpose of separating and purifying the clavulanic acid to the greatest extent is achieved.
The nonpolar macroporous adsorption resin can be nonpolar macroporous adsorption resin with the particle size of 400-1250 micrometers and the framework structure of styrene-divinylbenzene, for example, the nonpolar macroporous adsorption resin with the model LXT-053 produced by the new materials of Hill Lan Xiao technology. The resin is applied by wet packing in the form of a circular resin bed having a height to diameter ratio (i.e., height to diameter ratio) of 5 or more.
In the operation of step (1), it is necessary to strictly ensure that clavulanic acid is always in an operating environment of 0 ℃ to 20 ℃, preferably 0 ℃ to 5 ℃. Wherein, the nonpolar macroporous adsorption resin can specifically adsorb the clavulanic acid in an acidic environment, and the adsorption capacity of each liter of resin can reach 100-120 g of clavulanic acid. In order to ensure the maximum adsorption amount during the resin adsorption, the flow rate of the clavulanic acid aqueous solution to the column is strictly controlled, preferably 0.3 to 0.5BV/h (bed volume per hour) is passed through the resin bed. And impurities which are not adsorbed by the resin flow through the resin bed, and are collected and discharged for treatment. When clavulanic acid in the effluent of the resin bed leaks out, the resin adsorption is stopped. The resin is then initially washed with a stream of purified water, i.e., a washing resin, preferably in an amount of 4.0 to 6.0BV (bed volume), preferably at a flow rate of 1.0 to 2.0BV/h (bed volume per hour). Impurities which are not adsorbed on the resin column are removed by water washing, so that the quality of the clavulanic acid product is ensured to the greatest extent. Finally, the clavulanic acid adsorbed on the resin is resolved using a resolving agent which may be selected from the group consisting of aqueous potassium carbonate and aqueous potassium bicarbonate, preferably aqueous potassium bicarbonate, and the concentration of the aqueous potassium bicarbonate is preferably 0.5 to 1.0mol/L, more preferably 0.2 to 0.3mol/L, and converted into potassium clavulanate. The flow rate of the resolving agent passing through the resin bed is 0.5-1.0 BV/h, and the resolving liquid with the pH value of 5.0-7.0 at the outlet of the resin bed is collected to obtain the resolving liquid containing the potassium clavulanate. The concentration of the desorption solution is generally 30 to 50mg/mL in terms of clavulanic acid, and the liquid phase purity thereof is more than 95% (HPLC peak area percentage).
In the above manner, potassium ions in the resolving agent and clavulanic acid adsorbed on the resin are converted into potassium clavulanate, and then potassium clavulanate is eluted from the resin, while bicarbonate or carbonate in the resolving agent and hydrogen ions in the clavulanic acid are converted into carbon dioxide or water, and no new ion impurities are introduced. Meanwhile, the high enrichment of the clavulanate potassium is realized.
According to an embodiment of the present invention, in the method for producing potassium clavulanate of the present invention, in the decoloring and concentrating of the potassium clavulanate analyzing solution of step (2), the potassium clavulanate analyzing solution obtained in step (1) is passed through a hydrogen carbonate type anion exchange resin or a carbonic acid type anion exchange resin to obtain a decolored potassium clavulanate aqueous solution; the decolorized clavulanate potassium aqueous solution is concentrated by a high-pressure reverse osmosis membrane to obtain clavulanate potassium concentrated solution, wherein the anion exchange resin in the bicarbonate form is anion exchange resin in the bicarbonate form after alkali activation and treatment of potassium bicarbonate aqueous solution, and the anion exchange resin in the carbonate form is anion exchange resin in the carbonate form after alkali activation and treatment of potassium carbonate aqueous solution.
In the operation and running process of the step (2), the potassium clavulanate is required to be strictly ensured to be always in an operation environment of 0-20 ℃, preferably 0-5 ℃. Among them, the anion exchange resin used is preferably a weakly basic anion exchange resin, and for example, LXT-267 type anion exchange resin manufactured by Hill Lan Xiao New technology Co., ltd.
The anion exchange resin in the bicarbonate form is converted into the anion exchange resin in the bicarbonate form by alkali activation and treatment of aqueous solution of potassium bicarbonate. Specifically, the anion exchange resin in bicarbonate form is obtained by treating the transformation of the anion exchange resin according to the following method: activating the anion exchange resin by adopting sodium hydroxide solution or potassium hydroxide solution, and then flushing the anion exchange resin by using purified water until the eluate is neutral and the conductivity is lower than 50 mu s/cm; then, the resin is converted into bicarbonate ions by treatment with 1.0 to 2.0mol/L aqueous potassium bicarbonate solution, followed by washing with purified water until the eluate is free of potassium bicarbonate and has a conductivity below 50. Mu.s/cm. Thus, the radicals on the anion exchange resin are thoroughly replaced by bicarbonate, and redundant potassium bicarbonate is cleaned and removed, so that degradation of potassium clavulanate caused by pH fluctuation in the feeding process is avoided.
The carbonic acid type anion exchange resin is converted into carbonic acid type anion exchange resin through alkali activation and treatment of potassium carbonate aqueous solution. Specifically, the carbonic acid type anion exchange resin is obtained by treating the transformation of the anion exchange resin according to the following method: activating the anion exchange resin by adopting sodium hydroxide solution or potassium hydroxide solution, and then flushing the anion exchange resin by using purified water until the eluate is neutral and the conductivity is lower than 50 mu s/cm; then, the resin is converted to carbonate ion by treating it with 1.0 to 2.0mol/L aqueous potassium carbonate solution, followed by washing with purified water until the eluate is free of potassium carbonate and has a conductivity below 50. Mu.s/cm. Thus, the radicals on the anion exchange resin are thoroughly replaced by carbonate, and the redundant potassium carbonate is cleaned and removed, so that the degradation of the potassium clavulanate caused by the fluctuation of pH in the feeding process is avoided.
Specifically, the potassium clavulanate analysis solution obtained in the step (1) is decolorized by a bicarbonate type anion exchange resin or a carbonic acid type anion exchange resin column bed at a flow rate of 1-2 BV/h (volume per hour), column outlet effluent with a light transmittance of more than or equal to 98% is collected, namely decolorized aqueous solution containing potassium clavulanate, the concentration of the collected decolorized aqueous solution of potassium clavulanate is 30-50 mg/mL calculated by clavulanate, and the liquid phase purity is more than 99% (HPLC peak area percentage).
Then, the decolorized aqueous solution of potassium clavulanate was concentrated using a high pressure reverse osmosis membrane to obtain a concentrated solution of potassium clavulanate. The high pressure reverse osmosis membrane is a composite membrane composed of a polyester non-woven fabric layer, a polysulfone porous middle support layer and a polyamide separation layer, for example, FILMTEC produced by Dow chemical production can be selected TM Model membrane. The concentration of the potassium clavulanate concentrate obtained after concentration by using the high-pressure reverse osmosis membrane can reach 240-260 mg/mL based on clavulanic acid, the liquid phase purity is more than 98 percent (HPLC peak area percent), and the light transmittance of the concentrate is high≥95％。
According to one embodiment of the present invention, in the method for producing clavulanate potassium of the present invention, in the step (3) of producing clavulanate potassium, the clavulanate potassium concentrate obtained in the step (2) is freeze-dried to obtain clavulanate potassium crystal having a quality conforming to the standard.
In the freeze-drying process of the potassium clavulanate concentrated solution, the inventor designs and obtains proper processes in freezing, primary drying and analytical drying stages in the freeze-drying process through repeated experiments and groping, including temperature design, temperature rising design, time design and vacuum design, according to the following freeze-drying process, the potassium clavulanate solution can be ensured to be frozen and not to melt in the sublimation process, the water in the potassium clavulanate solution is removed at the maximum sublimation rate, the obtained potassium clavate crystal has high and stable quality, and all indexes can meet the EP standard, wherein the content is 81-85.6%, the water content is less than or equal to 0.5%, the impurity E is less than or equal to 1.0%, the impurity G is less than or equal to 1.0%, the maximum unknown single impurity is less than or equal to 0.2%, and the total impurity is less than or equal to 2.0%.
TABLE 1 Freeze drying process
The method for producing potassium clavulanate according to the present invention will be described more specifically by examples, but the scope of the present invention is not limited to these examples.
In the following examples, potassium clavulanate yield is defined as: the relative amounts of clavulanic acid potassium crystal weight/clavulanic acid content in the aqueous solution of clavulanic acid are expressed as percentages.
Treatment of resin before use
Pretreatment of nonpolar macroporous adsorption resin: activation with methanol followed by rinsing the resin with purified water until no methanol odor;
the anion exchange resin bicarbonate is obtained by treating the transformation of the anion exchange resin according to the following method: activating the anion exchange resin with 4-5% (w/v) sodium hydroxide solution, and then washing with purified water until the eluate is neutral and the conductivity is below 50 μs/cm; then, the resin is converted to bicarbonate form by treatment with 1.0 to 2.0mol/L aqueous potassium bicarbonate solution, followed by washing with purified water until the eluate is free of potassium bicarbonate and has a conductivity below 50 μs/cm.
Example 1
(1) Adsorption, resolution and conversion of clavulanic acid
Acidifying the aqueous solution of clavulanic acid with 25% (v/v) hydrochloric acid at 3+ -2deg.C, wherein the clavulanic acid content is 1.5mg/mL, the pH is 0.75, the acidified aqueous solution of clavulanic acid is passed through a macroporous adsorbent resin bed (LXT-053 resin, loading 1L, height to diameter ratio of 5) at a flow rate of 0.5BV/h, the total loading amount is 80L, and after loading, the resin column is washed with 5L of purified water at a flow rate of 1.0 BV/h; then 0.2mol/L potassium bicarbonate solution is used for resolving the clavulanic acid adsorbed on the resin at the flow rate of 0.5BV/h, the desorption liquid with the pH value of more than or equal to 5.0 and less than or equal to 7.0 at the outlet of the resin bed is collected, 3.2L of potassium clavulanate desorption liquid is collected after the desorption is finished, the concentration is 36.5mg/mL calculated by the clavulanic acid, and the liquid phase purity is 95.8%.
(2) Decoloring and concentrating the potassium clavulanate analytic solution
Decolorizing the potassium clavulanate analytic solution obtained in the step (1) through a bicarbonate anion exchange resin column bed at a flow rate of 1BV/h (LXT-267 resin, 1L loading and 5 height-diameter ratio) at a temperature of 3+/-2 ℃, and collecting column outlet effluent with a light transmittance of 98% or more, namely 3.2L of decolorized potassium clavulanate aqueous solution, wherein the concentration is 35.6mg/mL calculated by clavulanic acid, and the liquid phase purity is 99.3%;
adopts a high-pressure reverse osmosis membrane (FILMTEC) TM Model number) the decolorized potassium clavulanate aqueous solution is concentrated to obtain 465mL of potassium clavulanate concentrated solution, wherein the concentration is 245mg/mL calculated by clavulanate, the liquid phase purity is 98.2%, and the light transmittance is more than or equal to 96.7%.
(3) Preparation of Potassium clavulanate
The potassium clavulanate concentrate is freeze-dried by adopting the following freeze-drying process, and 135.8 g of potassium clavulanate is obtained, and the product yield is as follows: 113.2%. The content of clavulanic acid is 83.7%, the water content is 0.20%, the impurity E is 0.006%, the impurity G is 0.001%, the maximum unknown single impurity is 0.026%, the total impurity is 0.19%, and the product quality meets the EP standard.
Example 2
(1) Adsorption, resolution and conversion of clavulanic acid
Acidifying the aqueous solution of clavulanic acid with 25% (v/v) hydrochloric acid at 3+ -2deg.C, wherein the clavulanic acid content is 1.3mg/mL, the pH is 0.75, the acidified aqueous solution of clavulanic acid is passed through a macroporous adsorbent resin bed (LXT-053 resin, loading 1L, height to diameter ratio of 5) at a flow rate of 0.3BV/h, the total loading amount is 92L, and after loading, the resin column is washed with 6L of purified water at a flow rate of 1.0 BV/h; then, the clavulanic acid adsorbed on the resin was analyzed by using a 0.2mol/L potassium bicarbonate solution at a flow rate of 0.5BV/h, a desorption solution having a pH of 5.0 or more and 7.0 or less was collected at the outlet of the resin bed, 3.0L of the clavulanate potassium desorption solution was collected after the desorption, and the concentration was 39.0mg/mL in terms of clavulanic acid, and the purity of the liquid phase was 95.2%.
(2) Decoloring and concentrating the potassium clavulanate analytic solution
Decolorizing the potassium clavulanate analytic solution obtained in the step (1) through a bicarbonate anion exchange resin column bed at a flow rate of 1BV/h (LXT-267 resin, 1L loading and 5 height-diameter ratio) at a temperature of 3+/-2 ℃, and collecting column outlet effluent with a light transmittance of 98% or more, namely 3.0L of decolorized potassium clavulanate aqueous solution, wherein the concentration is 38.2mg/mL calculated by clavulanic acid, and the liquid phase purity is 99.1%;
adopts a high-pressure reverse osmosis membrane (FILMTEC) TM Model number) the decolorized potassium clavulanate aqueous solution is concentrated to obtain 455mL of potassium clavulanate concentrate, wherein the concentration is 252mg/mL calculated by clavulanic acid, the liquid phase purity is 98.1%, and the light transmittance is more than or equal to 96.3%.
(3) Preparation of Potassium clavulanate
The potassium clavulanate concentrate was freeze-dried using the same lyophilization process as in example 1 to obtain 136.7 g of potassium clavulanate with the following product yield: 114.3%. The content of clavulanic acid is 83.6%, the water content is 0.22%, the impurity E is 0.008%, the impurity G is 0.002%, the maximum unknown single impurity is 0.029%, the total impurities are 0.23%, and the product quality meets the EP standard.
Example 3
(1) Adsorption, resolution and conversion of clavulanic acid
Acidifying the clavulanic acid aqueous solution with 15% (v/v) sulfuric acid at 3+ -2deg.C, wherein the clavulanic acid content is 1.9mg/mL, the pH is 0.75, the acidified clavulanic acid aqueous solution passes through a macroporous adsorbent resin column bed (LXT-053 resin, loading amount is 1L, height to diameter ratio is 5) at a flow rate of 0.5BV/h, the total column loading amount is 63L, 4L of purified water is used after the column loading is completed, and the resin column is washed at a flow rate of 1.0 BV/h; then 0.2mol/L potassium bicarbonate solution is used for resolving the clavulanic acid adsorbed on the resin at the flow rate of 0.5BV/h, the desorption liquid with the pH value of more than or equal to 5.0 and less than or equal to 7.0 at the outlet of the resin bed is collected, 2.9L of potassium clavulanate desorption liquid is collected after the desorption, the concentration is 40.5mg/mL calculated by the clavulanic acid, and the liquid phase purity is 96.7 percent.
(2) Decoloring and concentrating the potassium clavulanate analytic solution
Decolorizing the potassium clavulanate analytic solution obtained in the step (1) through a bicarbonate anion exchange resin column bed at a flow rate of 1BV/h (LXT-267 resin, 1L loading and 5 height-diameter ratio) at a temperature of 3+/-2 ℃, and collecting column outlet effluent with a light transmittance of 98% or more, namely 2.9L of decolorized potassium clavulanate aqueous solution, wherein the concentration is 39.9mg/mL calculated by clavulanic acid, and the liquid phase purity is 99.6%;
adopts a high-pressure reverse osmosis membrane (FILMTEC) TM Model number) and concentrating the decolorized potassium clavulanate aqueous solution to obtain 454mL of potassium clavulanate concentrated solution, wherein the concentration is 255mg/mL calculated by clavulanic acid, the liquid phase purity is 98.7%, and the light transmittance is more than or equal to 97.2%.
(3) Preparation of Potassium clavulanate
The potassium clavulanate concentrate was freeze-dried using the same lyophilization process as in example 1 to give 138.2 g of potassium clavulanate with the following product yield: 115.4%. The content of clavulanic acid is 83.8%, the water content is 0.17%, the impurity E is 0.003%, the impurity G is 0.001%, the maximum unknown single impurity is 0.018%, the total impurities are 0.17%, and the product quality meets the EP standard.
Claims (10)
1. A method for preparing potassium clavulanate, comprising the steps of:
(1) Adsorption, resolution and conversion of clavulanic acid
Acidizing an aqueous solution of clavulanic acid, adsorbing the clavulanic acid on the resin through nonpolar macroporous adsorption resin, washing the resin by using purified water, and then resolving the clavulanic acid adsorbed on the resin by using a resolving agent to convert the clavulanic acid into potassium clavulanate to obtain potassium clavulanate resolving solution;
wherein the desorbent is selected from the group consisting of aqueous potassium carbonate and aqueous potassium bicarbonate;
(2) Decoloring and concentrating the potassium clavulanate analytic solution
Passing the potassium clavulanate analytic solution obtained in the step (1) through bicarbonate anion exchange resin or carbonic acid anion exchange resin to obtain decolorized potassium clavulanate aqueous solution; concentrating the decolorized potassium clavulanate aqueous solution through a high-pressure reverse osmosis membrane to obtain potassium clavulanate concentrated solution;
wherein the carbonic acid type anion exchange resin is changed into carbonic acid type anion exchange resin through alkali activation and potassium bicarbonate water solution treatment, and the carbonic acid type anion exchange resin is changed into carbonic acid type anion exchange resin through alkali activation and potassium carbonate water solution treatment;
(3) Preparation of Potassium clavulanate
And (3) freeze-drying the potassium clavulanate concentrate obtained in the step (2) to obtain potassium clavulanate crystals.
2. The method for producing potassium clavulanate according to claim 1, wherein the aqueous solution of clavulanic acid has a concentration of 1.0 to 2.0mg/mL and a pH of 5.0 to 6.0.
3. The method for producing potassium clavulanate according to claim 1 or 2, characterized in that in the adsorption, desorption and conversion of clavulanic acid in the step (1), the acidification treatment of the aqueous solution of clavulanic acid is carried out at a temperature of 0 ℃ to 20 ℃ by sulfuric acid or hydrochloric acid, and the pH of the aqueous solution of clavulanic acid after the acidification treatment is 0.5 to 1.0.
4. The method for preparing potassium clavulanate according to claim 3, wherein the nonpolar macroporous adsorption resin has a particle size of 400-1250 μm and a skeleton structure of styrene-divinylbenzene; the acidified clavulanic acid aqueous solution passes through a nonpolar macroporous adsorption resin bed at the flow rate of 0.3-0.5 BV/h, and resin adsorption is stopped when clavulanic acid in effluent liquid of the resin bed leaks out; then washing the resin with purified water, wherein the consumption of the purified water is 4.0-6.0 BV, and the flow rate is 1.0-2.0 BV/h; then resolving clavulanic acid adsorbed on the resin by using a resolving agent, converting the clavulanic acid into potassium clavulanate, wherein the flow rate of the resolving agent is 0.5-1.0 BV/h, collecting the desorption liquid with the pH value of 5.0-7.0 at the outlet of the resin bed, and obtaining the desorption liquid containing potassium clavulanate.
5. The method according to claim 4, wherein the concentration of clavulanate potassium in the clavulanate potassium analysis solution is 30 to 50mg/mL in terms of clavulanic acid, and the purity of the liquid phase is more than 95%.
6. The process for producing potassium clavulanate according to claim 1 or 2, characterized in that, in the step (2) of decoloring and concentrating the potassium clavulanate analyzing solution, the potassium clavulanate analyzing solution obtained in the step (1) is decolored by passing through a hydrogencarbonate anion exchange resin or a carbonic acid anion exchange resin column bed at a flow rate of 1 to 2BV/h at a temperature of 0 to 20 ℃, and the column outlet effluent with a light transmittance of 98% or more is collected to obtain a decolored aqueous solution containing potassium clavulanate, the concentration of the collected decolored aqueous solution of potassium clavulanate is 30 to 50mg/mL in terms of clavulanate, and the liquid phase purity is more than 99%.
7. The method for preparing potassium clavulanate according to claim 6, wherein the anion exchange resin used is a weakly basic anion exchange resin;
the anion exchange resin in the bicarbonate form is obtained by converting the anion exchange resin according to the following method: activating the anion exchange resin by adopting sodium hydroxide solution or potassium hydroxide solution, and then flushing the anion exchange resin by using purified water until the eluate is neutral and the conductivity is lower than 50 mu s/cm; then, treating the resin with 1.0-2.0 mol/L potassium bicarbonate aqueous solution to convert the resin into bicarbonate ions, and then washing the resin with purified water until the eluate does not contain potassium bicarbonate and has conductivity lower than 50 mu s/cm;
the carbonic acid type anion exchange resin is obtained by treating anion exchange resin transformation according to the following method: activating the anion exchange resin by adopting sodium hydroxide solution or potassium hydroxide solution, and then flushing the anion exchange resin by using purified water until the eluate is neutral and the conductivity is lower than 50 mu s/cm; then, the resin is converted to carbonate ion by treating it with 1.0 to 2.0mol/L aqueous potassium carbonate solution, followed by washing with purified water until the eluate is free of potassium carbonate and has a conductivity below 50. Mu.s/cm.
8. The method for producing potassium clavulanate according to claim 1 or 2, characterized in that in the decolorization and concentration of the potassium clavulanate analyzing solution of step (2), the decolorized potassium clavulanate aqueous solution is concentrated by using a high-pressure reverse osmosis membrane at a temperature of 0 ℃ to 20 ℃ to obtain a potassium clavulanate concentrate; the high-pressure reverse osmosis membrane is a composite membrane composed of a polyester non-woven fabric layer, a polysulfone porous middle supporting layer and a polyamide separating layer.
9. The process for producing potassium clavulanate according to claim 8, wherein the concentration of the obtained potassium clavulanate concentrate is 240 to 260mg/mL in terms of clavulanic acid, and the purity of the liquid phase is more than 98%.
10. The method for producing potassium clavulanate according to claim 1 or 2, characterized in that in the step (3) of producing potassium clavulanate, the freeze-drying process is as follows:
。
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| ES436766A1 (en) * | 1974-04-20 | 1977-08-16 | Beecham Group Ltd | A procedure for the preparation of a clavulan acid salt. (Machine-translation by Google Translate, not legally binding) |
| WO1997005142A1 (en) * | 1995-08-02 | 1997-02-13 | Smithkline Beecham P.L.C. | Process for the preparation of potassium clavulanate |
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| ES436766A1 (en) * | 1974-04-20 | 1977-08-16 | Beecham Group Ltd | A procedure for the preparation of a clavulan acid salt. (Machine-translation by Google Translate, not legally binding) |
| WO1997005142A1 (en) * | 1995-08-02 | 1997-02-13 | Smithkline Beecham P.L.C. | Process for the preparation of potassium clavulanate |
| CN101279982A (en) * | 2008-05-29 | 2008-10-08 | 鲁南制药集团股份有限公司 | Novel method for preparing clavulanate |
| CN104673872A (en) * | 2014-12-31 | 2015-06-03 | 西安蓝晓科技新材料股份有限公司 | Method for recycling DCPC (deacetyl cephalosporin C) from cephalosporin C resin adsorption waste liquor |
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