CN110642900A - Tetracycline extraction and purification method - Google Patents
Tetracycline extraction and purification method Download PDFInfo
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- CN110642900A CN110642900A CN201911073602.9A CN201911073602A CN110642900A CN 110642900 A CN110642900 A CN 110642900A CN 201911073602 A CN201911073602 A CN 201911073602A CN 110642900 A CN110642900 A CN 110642900A
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- tetracycline
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- purifying
- ceramic membrane
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- 229930101283 tetracycline Natural products 0.000 title claims abstract description 69
- 239000004098 Tetracycline Substances 0.000 title claims abstract description 68
- 229960002180 tetracycline Drugs 0.000 title claims abstract description 68
- 235000019364 tetracycline Nutrition 0.000 title claims abstract description 68
- 150000003522 tetracyclines Chemical class 0.000 title claims abstract description 65
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000000746 purification Methods 0.000 title abstract description 13
- 238000000605 extraction Methods 0.000 title abstract description 8
- 238000000855 fermentation Methods 0.000 claims abstract description 38
- 230000004151 fermentation Effects 0.000 claims abstract description 38
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012528 membrane Substances 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000000919 ceramic Substances 0.000 claims abstract description 11
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229960001763 zinc sulfate Drugs 0.000 claims abstract description 10
- 229910000368 zinc sulfate Inorganic materials 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 235000012247 sodium ferrocyanide Nutrition 0.000 claims abstract description 8
- 238000010790 dilution Methods 0.000 claims abstract description 7
- 239000012895 dilution Substances 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000000926 separation method Methods 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 33
- 238000010828 elution Methods 0.000 claims description 15
- 230000020477 pH reduction Effects 0.000 claims description 12
- 235000006408 oxalic acid Nutrition 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 10
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 claims description 5
- 230000001580 bacterial effect Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 2
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 239000012943 hotmelt Substances 0.000 claims 1
- 239000012629 purifying agent Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 10
- 239000012535 impurity Substances 0.000 description 9
- 238000002156 mixing Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000005374 membrane filtration Methods 0.000 description 4
- 241000186984 Kitasatospora aureofaciens Species 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- -1 tetra-D tetracycline Chemical class 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000192142 Proteobacteria Species 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000011218 seed culture Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a tetracycline extraction and purification method, which comprises the following process steps: firstly, adding water to tetracycline fermentation liquor for dilution, cooling and acidifying, then separating by using a ceramic membrane, sequentially adding yellow blood salt and zinc sulfate into the obtained filter washing liquor at an interval of 5-10min, stirring for reaction, then filtering by using a plate frame, introducing alkali for crystallization, and finally filtering, dehydrating and drying to obtain a tetracycline finished product. According to the invention, diluted and acidified tetracycline fermentation liquor is separated by adopting the ceramic membrane, and then the tetracycline is extracted and purified in a purification and separation mode, so that the quality of the tetracycline is obviously improved, the yield is improved by 3-5%, the use of a purifying agent is reduced, the membrane operation efficiency is improved, and the production cost is reduced.
Description
Technical Field
The invention belongs to the technical field of biology and new medicines, and particularly relates to a tetracycline extraction and purification method.
Background
Tetracycline (Er) is a tetracyclic antibiotic, has good inhibitory action on gram-positive bacteria, gram-negative bacteria, rickettsia, filterable viruses, spirochetes and protozoon, and is ineffective against tubercle bacillus, proteobacteria and the like. The mechanism of action is to prevent the aminoacyl-tRNA from binding to the ribosome after binding to the 30S subunit of the ribosome.
In the prior art, the tetracycline is produced by fermenting streptomyces aureofaciens in a two-stage fermentation mode, wherein the tetracycline can be extracted and purified by the following two methods: firstly, diluting tetracycline fermentation liquor, then carrying out one-time acidification and purification by oxalic acid, then carrying out plate-frame or membrane filtration, adjusting pH, and crystallizing and separating out to obtain a tetracycline base finished product; secondly, tetracycline is fermented and diluted, then the tetracycline is acidified by oxalic acid, filtered, the pH value is adjusted, calcium chloride is added to form calcium salt precipitate, then the calcium salt precipitate is dissolved by oxalic acid, the pH value is adjusted to separate out crude alkali, the crude alkali is dissolved by oxalic acid, the crude alkali is decolored by active carbon, and the pH value is adjusted to obtain a tetracycline alkali finished product.
At present, domestic tetracycline production enterprises generally adopt a first method for extracting and purifying tetracycline, and the method has the following problems: 1. the tetracycline fermentation liquor is acidified once, the storage time of the acidified liquor is long, and impurities such as tetra-D tetracycline and the like are easy to generate; 2. in the purification process, the concentration of tetracycline and impurities is higher, and the added purifying agent has adsorption and encapsulation effects on tetracycline while removing the impurities, so that the tetracycline is difficult to wash out by acid water in the filtration process; 3. the purification dosage is larger, so that the whole fermentation liquor becomes thick, the purification effect is weakened, the quality of filtrate is influenced, the filtration efficiency is further influenced, and the extraction quality and yield of tetracycline are finally influenced.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a tetracycline extraction and purification method which can effectively improve the content and yield of tetracycline finished products and reduce the production cost.
The technical scheme adopted for realizing the aim of the invention is as follows:
a method for extracting and purifying tetracycline is characterized by comprising the following process steps: firstly, adding water to tetracycline fermentation liquor for dilution, cooling, continuously acidifying, then separating by using a ceramic membrane, sequentially adding yellow blood salt and zinc sulfate into the obtained filter washing liquor at an interval of 5-10min, stirring for reacting, then filtering by using a plate frame, introducing alkali for crystallization, and finally filtering, dehydrating and drying to obtain a tetracycline finished product.
When the tetracycline is diluted by water, the water addition amount is 0.5-2.0 times of the volume of the fermentation liquor.
The cooling and continuous acidification means that the diluted tetracycline fermentation liquor is cooled to 10-20 ℃, then oxalic acid is fed in, the pH value of the fermentation liquor is controlled to be 1.5-2.0, and the acidification time is 5-10 minutes.
The aperture of the ceramic membrane is 50-100 nm, when the tetracycline fermentation liquor is concentrated by 1.5-2 times, oxalic acid water is added for elution, the temperature in the elution process is controlled at 10-20 ℃, and the process is stopped until the unit titer of the tetracycline bacterial residue is less than or equal to 1000 mu g/ml.
The yellow blood salt and the zinc sulfate are added in a hot melting way, and the adding amount of the yellow blood salt and the zinc sulfate is controlled to be 50-80 g/billion.
Compared with the prior art, the invention has the following technical advantages:
1. the invention firstly dilutes the tetracycline fermentation liquor and acidifies the tetracycline fermentation liquor in a continuous acidification mode, and the storage time of the acidizing liquor is shortened by controlling the acidification time, the temperature and the pH value in the process, thereby avoiding the degradation and the damage of the tetracycline and improving the product yield.
2. In the prior art, a purifying agent is added before membrane filtration for treatment, the concentration of tetracycline and impurities is higher in the purification process, and the added purifying agent can adsorb and wrap the tetracycline while removing the impurities, so that the tetracycline is difficult to wash out by using acid water in the filtration process; moreover, the added purifying agent is used in a large amount, so that the whole fermentation liquor is thickened, the purifying effect is weakened, the quality of filtrate is influenced, the filtering efficiency is influenced, and the extraction quality and yield of tetracycline are influenced finally. The invention adopts membrane filtration and then carries out purification treatment, and because the membrane filtration precision is high and the impurity interception effect is good, the concentration of tetracycline in the filtrate is reduced and the impurity content is low, the added purifying agent amount can be naturally reduced, the mixing effect is good, and the product quality is greatly improved by matching with continuous acidification.
In conclusion, the method provided by the invention not only obviously improves the quality of the tetracycline, but also improves the yield of the tetracycline by 3-5%, reduces the use of a purifying agent, improves the membrane operation efficiency and reduces the production cost.
Drawings
FIG. 1 is a process flow diagram of the tetracycline extraction and purification of the present invention.
Detailed Description
The technical solution of the present invention will be described in detail with reference to examples. It should be understood that the examples are intended to illustrate the invention and are not intended to limit the invention. The scope and core content of the invention are to be determined by the claims.
The tetracycline fermentation liquid in the following examples is prepared by the presently disclosed fermentation method, for example, fermentation liquid in a secondary fermentation mode with streptomyces aureofaciens as a fermentation strain, and the specific process is as follows: culturing a streptomyces aureofaciens strain (sand tube) through the slant spore of a mother bottle to obtain the slant spore of the mother bottle, culturing through the slant spore of a son bottle to obtain the slant spore of the son bottle, culturing through a seeding tank to obtain a seed culture solution, and culturing through a fermentation tank to obtain a fermentation liquid.
Example 1
Taking 20L tetracycline fermentation liquor, measuring the titer unit of the tetracycline fermentation liquor to be 30852 mug/mL, adding 10L primary water for dilution, stirring and mixing uniformly, cooling to 17 ℃, pumping the diluted fermentation liquor into a material mixer, simultaneously adding oxalic acid to control the pH of the fermentation liquor to be 1.5-2.0, controlling the acidification time to be 5-10min, feeding into a ceramic membrane with the pore diameter of 100nm, carrying out on-line continuous acidification release separation, beginning to add oxalic acid water with the pH of 1.72 for elution when the oxalic acid is concentrated to 1.5 times, controlling the temperature in the elution process to be 10-20 ℃, controlling the elution water amount to be 80L, finishing the elution, adding filter washing liquid to obtain 97L, adding 40g of yellow blood salt (hot dissolving) into the filtrate and washing liquid, adding 40g of zinc sulfate (hot dissolving), stirring for 5min, filtering and separating by adopting a plate frame to obtain a purified liquid, and controlling the temperature to be 5-10 ℃, adding 15-20% liquid alkali to regulate the pH value to be 4.6-4.8, stirring for 120min, and filtering, leaching, dehydrating and drying to obtain a tetracycline finished product.
Example 2
Taking 25L of tetracycline fermentation liquor, measuring the titer unit to 31200 mu g/mL, adding 12.5L of primary water for dilution, stirring and mixing uniformly, cooling to 16 ℃, pumping the diluted fermentation liquor into a material mixer, simultaneously adding oxalic acid to control the pH of the fermentation liquor to be 1.5-2.0, controlling the mixing time to be 5-10min, feeding into a ceramic membrane with the pore diameter of 100nm, carrying out on-line continuous acidification and release separation, beginning to add oxalic acid water with the pH of 1.75 for elution when the concentration is 1.6 times, controlling the temperature in the elution process to be 10-20 ℃, controlling the elution water amount to be 100L, finishing the elution, adding filter washing liquid to obtain 121.9L, controlling the average titer unit to be 8318 mu g/mL and billion 1.0, adding 60g of yellow blood salt (hot dissolution), stirring for 5min, adding 60g of zinc sulfate (hot dissolution), stirring for 5min, adopting a plate-frame filtration separation to obtain a purified liquid, controlling the temperature to be 5-10 ℃, adding 15-20% liquid alkali to adjust the pH to be 4, stirring for 120min, filtering, leaching, dehydrating and drying to obtain the tetracycline finished product.
Example 3
Taking 30L tetracycline fermentation liquor, measuring the titer unit to be 30085 mu g/mL, adding 15L primary water for dilution, stirring and mixing uniformly, cooling to 17 ℃, pumping the diluted fermentation liquor into a material mixer, simultaneously adding oxalic acid to control the pH of the fermentation liquor to be 1.5-2.0, controlling the mixing time to be 5-10min, feeding into a ceramic membrane with the pore diameter of 100nm, carrying out on-line continuous acidification release separation, beginning to add oxalic acid water with the pH of 1.78 for elution when the concentration is 1.7 times, controlling the temperature in the elution process to be 10-20 ℃, controlling the elution water amount to be 120L, finishing the elution, collecting filter washing liquid to obtain 147.4L, controlling the average titer unit to be 7960 mu g/mL and ten billion 1.17, adding 93.6g of yellow blood salt (hot dissolving), stirring for 5min, adding 93.6g of zinc sulfate (hot dissolving), stirring for 5min, filtering and separating by adopting a plate frame to obtain a purified liquid, controlling the temperature to be 5-10 ℃, adding 15-20% liquid alkali to adjust the pH to be 4, stirring for 120min, filtering, leaching, dehydrating and drying to obtain the tetracycline finished product.
Comparative example
Taking 30L of tetracycline fermentation liquor, determining the titer unit to be 30030 mu g/mL, adding 15L of primary water for dilution, stirring and mixing uniformly, cooling to 17 ℃, adding oxalic acid to adjust the pH value of the fermentation liquor to 1.8, stirring for 30 minutes, sequentially adding the xanthate, the zinc sulfate and the borax at intervals of 10min (soaking solution addition), separating by using a ceramic membrane with the aperture of 100nm, controlling the temperature to be 5-10 ℃, adding 15-20% liquid alkali to adjust the pH value to be 4.6-4.8, stirring for 120min, and filtering, leaching, dehydrating and drying to obtain a tetracycline finished product.
FIG. 1: quality comparison of the invention with the comparative example
4-ETC | TC | 4-EATC | ATC | Ash content | |
Example 1 | 3.5 | 94.5 | 0 | 0.06 | 0.19 |
Example 2 | 3.4 | 94.2 | 0 | 0.05 | 0.25 |
Example 3 | 3.42 | 95 | 0 | 0.11 | 0.20 |
Comparative example | 4.7 | 91.3 | 0 | 0.13 | 0.22 |
Quality standard | ≤5.0 | 88.0~102 | ≤0.5 | ≤1.0 | ≤0.5 |
In FIG. 1, 4-ETC means 4-anhydrotetracycline, ATC means anhydrotetracycline, and 4-EATC means 4-anhydrotetracycline, which is a degradation product (impurity) of tetracycline, is dehydrated. TC is the content (active ingredient) of tetracycline. Generally, the quality improvement mainly means that the content of active ingredients is increased and the content of related substances (impurities) is reduced. As can be seen from FIG. 1, examples 1, 2 and 3 all show a different degree of reduction in 4-ETC and ATC compared to the comparative examples, while the TC value is significantly increased. Fully shows that the quality of the tetracycline is improved by improving the experimental process.
Claims (5)
1. A method for extracting and purifying tetracycline is characterized by comprising the following process steps: firstly, adding water to tetracycline fermentation liquor for dilution, cooling, continuously acidifying, then separating by using a ceramic membrane, sequentially adding yellow blood salt and zinc sulfate into the obtained filter washing liquor at an interval of 5-10min, stirring for reacting, then filtering by using a plate frame, introducing alkali for crystallization, and finally filtering, dehydrating and drying to obtain a tetracycline finished product.
2. The method for extracting and purifying tetracycline according to claim 1, characterized in that when the tetracycline is diluted with water, the amount of water added is 0.5-2.0 times the volume of the fermentation broth.
3. The method for extracting and purifying tetracycline according to claim 1, wherein the cooling and continuous acidification are to cool the diluted tetracycline fermentation broth to 10-20 ℃, and then to add oxalic acid, controlling the pH of the fermentation broth to 1.5-2.0, and the acidification time to 5-10 minutes.
4. The method for extracting and purifying tetracycline according to claim 1, characterized in that the aperture of the ceramic membrane is 50-100 nm, when the tetracycline fermentation broth is concentrated by 1.5-2 times during the ceramic membrane separation, the oxalic acid water added in the flow is eluted, and the temperature in the elution process is controlled to be 10-20 ℃ until the unit titer of tetracycline bacterial residue is less than or equal to 1000 μ g/ml.
5. The method for extracting and purifying tetracycline according to claim 1, characterized in that the said salts of yellow blood and zinc sulfate are added in hot melt, and the amount of the added salts is controlled to be 50-80 g/billion.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES323059A1 (en) * | 1965-07-30 | 1966-12-01 | Pereira Da Luz Artur | Extraction and purification of tetracycline from fermentation broths |
CN103086914A (en) * | 2012-12-20 | 2013-05-08 | 厦门市天泉鑫膜科技股份有限公司 | Membrane-method continuous extraction equipment and extraction process of tetracycline fermentation liquor |
CN104342477A (en) * | 2014-11-03 | 2015-02-11 | 金河生物科技股份有限公司 | Preparation method for tetracycline |
-
2019
- 2019-11-06 CN CN201911073602.9A patent/CN110642900A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES323059A1 (en) * | 1965-07-30 | 1966-12-01 | Pereira Da Luz Artur | Extraction and purification of tetracycline from fermentation broths |
CN103086914A (en) * | 2012-12-20 | 2013-05-08 | 厦门市天泉鑫膜科技股份有限公司 | Membrane-method continuous extraction equipment and extraction process of tetracycline fermentation liquor |
CN104342477A (en) * | 2014-11-03 | 2015-02-11 | 金河生物科技股份有限公司 | Preparation method for tetracycline |
Non-Patent Citations (2)
Title |
---|
叶勇 等: "《制药学工艺》", 28 February 2014 * |
李永丽: "土霉素酸化提取工艺的研究", 《内蒙古石油化工》 * |
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Application publication date: 20200103 |