CN105819444A - Composite type activated carbon and application thereof in purifying tacrolimus - Google Patents
Composite type activated carbon and application thereof in purifying tacrolimus Download PDFInfo
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- CN105819444A CN105819444A CN201610172215.0A CN201610172215A CN105819444A CN 105819444 A CN105819444 A CN 105819444A CN 201610172215 A CN201610172215 A CN 201610172215A CN 105819444 A CN105819444 A CN 105819444A
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- C01B32/00—Carbon; Compounds thereof
- C01B32/30—Active carbon
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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Abstract
The invention relates to the technical field of drug preparation and discloses composite type activated carbon and the application thereof in purifying tacrolimus. Through fermentation broth filtration, drying, digestion, extraction and washing, composite type activated carbon decoloration and decontamination, and crystal purification, the problems of existing tacrolimus purifying methods that purification yield is low, time consumption is high, elution solvent consumption is high, pollution is serious, and industrialized production can not be achieved easily are solved. By the adoption of the composite type activated carbon and the application thereof in purifying tacrolimus, large-scale production can be achieved easily, solvent consumption is low, production cycle is short, an obtained tacrolimus crude product is high in purity and is white or off-white color powder, weight fraction is 85% or more, and HPLC normalized concentration is 90% or more.
Description
Technical field
The present invention relates to a kind of technical field of medicine preparation, be specifically related to a kind of compound activated carbon and preparation thereof and the application in purification of tacrolimus.
Background technology
Tacrolimus is the macrolide immunosuppressants of a kind of novel potent, entitled Prograf (Prograf) the tacrolimus capsules agent of Japan's exploitation in 1991 and injection official listing, for Primary Hepatic transplant and renal transplantation rejection treatment, after be approved for again bone marrow transplantation.Tacrolimus formulations is in more than 80 country's listings such as China, Japan, the U.S. at present, is widely used in the treatment of the immunologic rejection after the solid organ transplantations such as liver, pancreas, kidney, heart and lung.Within 1999, Tacrolimus paste throws in Japanese market, for treating the atopic dermatitis of adult.
Tacrolimus is isolated tunning from streptomyces (streptomycestsukubaensis), and sweat also creates multiple tacrolimus analog, the impurity such as including dihydro tacrolimus and ascosin simultaneously；These impurity and tacrolimus structure are very much like, and physicochemical properties are close, are difficult to obtain the crude drug of higher degree by conventional purification technique, thus are difficult to meet market demand.Refine tacrolimus although the existing document isolated and purified about tacrolimus all discloses with adsorbent resin or modified silica-gel or high-speed countercurrent chromatography, but there is the problem that purification yield is low, industrialization cost is high.
Owing to tacrolimus structure is complicated, chiral radicals is the most, and its fermentation liquid has a lot of isomer and analog, such as dihydro tacrolimus, ascosin etc., the existence of these materials makes tacrolimus use conventional isolation and purification method cannot be kept completely separate and reach corresponding purity.
Chinese invention patent CN85109492, disclose a kind of by macroporous adsorbent resin HP20, silica gel, activated carbon prepares the method for FK506 crude product: a. extraction: carry out, with organic solvent, the mycelium that soaking fermentation liquid is filtrated to get, filter to obtain lixiviating solution, b. absorption and desorbing: put into resin HP20 absorption in lixiviating solution, the mixed solvent eluting of organic solvent and water, collection liquid concentrates, c. extraction: add the hydrophobic solvent extractions such as ethyl ester in concentrated solution, extract concentrates, d. silica gel column chromatography: extraction concentrated solution passes through silicagel column, with ethyl ester normal hexane mixed liquor eluting, collect eluent and be concentrated to give crude product.
U.S. patent Nos US2012065393 (A1), disclose a kind of method preparing FK506 crude product: a. extraction: with alcohol, ketone, based organic solvent carrys out the mycelium that soaking fermentation liquid is filtrated to get, filter to obtain lixiviating solution, b. back extraction: add halo alkanes in lixiviating solution and carry out back extraction, extract concentrates, c. column chromatography: cross silicagel column after extraction concentrated solution dilution or alumina column removes pigment and oils and fats, d. crystallization: collect eluent and be concentrated into certain volume addition deionized water, stirring decrease temperature crystalline, e. the wet crystalline substance filtered, wash with alkane, dry to obtain crude product, crude product purity is between 92～95%, yield is between 70～75%.
Chinese invention patent CN200580043951.6, a kind of method disclosing purifying tacrolimus, wherein use organic solvent eluting after the absorption of macrolide sample resins, organic solvent is selected from THF, acetonitrile, normal propyl alcohol, isopropanol, ethanol and acetone, collect the middle fraction of eluent, collecting the macrolide purified, crystallization uses ethyl acetate, hexamethylene and the three-phase system of water.
Chinese invention patent CN200910146385, disclose one and streptomycete fermentation liquid filter press is obtained thalline, thalline is extracted by organic solvent repeatedly room temperature, obtain lixiviating solution, macroporous resin and silica gel column chromatography is carried out after being concentrated by lixiviating solution, column chromatography gained tacrolimus mixed solvent carries out condensing crystallizing, and the purity of tacrolimus reaches 96.5%.
Above purification process all uses the method for positive or reversed phase column chromatography to obtain crude product, need to special equipment, consume substantial amounts of organic solvent, produce substantial amounts of waste water, waste liquid, disused stuffing material such as silica gel etc., wherein eluting solvent such as normal hexane, alkyl halide etc. is big to human toxicity, technique is the longest, operates complicated and dangerous.
Chinese invention patent CN200480008682.5, disclose crystallization and the purification process of a kind of macrolides, extract with polar solvent such as isobutyl acetate, ethyl acetate, gained extract obtains grease concentrate after adding water or methanol～water～the washing of normal hexane system, concentration, then with polar solvent, hydrocarbon solvent and the aqueous solution containing alkali, recrystallization, it is thus achieved that the crude product of macrocyclic lactone such as tacrolimus, but the purity obtaining crude product is low, and highest purity is 85.03%；Although the method does not use column chromatography purification, but needs to be further purified the requirement that can be only achieved drug standard.
Therefore, this area is badly in need of that a kind of simple to operate, with short production cycle, purity and yield are high, eluting solvent consumption is few, environmental protection, is beneficial to the purifying crude method of industrialized great production.
Summary of the invention
The purpose of the present invention is contemplated to overcome purifies and separates tacrolimus fermentation liquid impurity in prior art many, separating difficulty is big, the deficiency that existing purification process length complicated, time-consuming, purity and yield are low, provide a kind of compound activated carbon and the application in purification of tacrolimus thereof, solve the length low, time-consuming of purification yield in existing purification process, eluting solvent consumption is big, pollute high, to be unfavorable for industrialized great production problem.
In order to solve above-mentioned technical problem, the present invention is addressed by following technical proposals:
A kind of compound activated carbon, the specific surface area of described compound activated carbon is 800～1000m2/ g, aperture is 2.0～8.0nm, and the volume in hole is 0.5～1.0cm3/g。
This compound activated carbon specific surface area size can meet good decolorizing effect, can take into account again the rate of filtration smoothly, if specific surface area is too big, corresponding compound activated carbon granule is the least, easily blocks when filtering, is unfavorable for industrialized great production；Specific surface is the least, and decolouring impurity-eliminating effect is the most weak；This pore diameter range can preferably be taken into account decolouring and remove the effect of interference crystalline impurities, if aperture is less than 2nm, and the little Molecular Adsorption being mainly used in Gas Phase Adsorption or liquid phase, more weak to macromolecules adsorption；If aperture is more than 8.0nm, macromolecules adsorption effect is preferable, but little Molecular Adsorption decreased effectiveness, it is impossible to play decolouring impurity-eliminating effect.
Present invention also offers the preparation method of a kind of compound activated carbon, comprise the steps:
1) wood flour screening and be dried
Filtering out the wood flour that particle diameter is 6～40 mesh, at the hot-air of 120～150 DEG C, wood flour is carried out pneumatic conveying drying, dried wood flour moisture content is 15～20%；Described hot-air flow velocity is 6～10 meter per seconds, preferably 8 meter per seconds.
2) compound concentration is the alkaline aqueous solution of 65～75%.
3) kneading
By step 1) in dried wood flour and step 2) knead under neutral and alkali aqueous solution stirring condition；The weight of described wood flour and the weight ratio of alkaline aqueous solution are 0.8～1.2:1, preferably 1:1.
This kneading operation is to by wood flour and alkaline aqueous solution, not stop stirring by a pair zigzag stirring paddle in kneading machine, repeatedly rub pressure, make they mix homogeneously, accelerate alkaline aqueous solution to wood flour internal penetration.
4) wood flour carbonization and activation
By step 3) in kneading after wood flour carbonization 0.5～1.5h, preferably 1.0h under nitrogen protection, carbonization temperature is 250～300 DEG C, preferably 280 DEG C；Then by wood flour at 700～900 DEG C, preferably 800 DEG C activation, soak time 2.0h.
5) reclaim
By wood flour after activation with 40～the hydrochloric acid solution washing of 50%, then clean with the hot water of 90～100 DEG C；
6) centrifuge dehydration, being dried to moisture content 4～6%, last pulverizing is compound activated carbon.
As preferably, step 1) described in wood flour to be dried front moisture content be 40%；Step 2) described in alkaline aqueous solution be sodium hydroxide, potassium hydroxide aqueous solution.
Present invention also offers the application in purification of tacrolimus of a kind of compound activated carbon.
Present invention also offers a kind of compound activated carbon for the method for purification of tacrolimus, comprise the steps:
1) fermentation liquor pretreatment: first by tacrolimus filtering fermentation liquor, extract, extract, wash after, it is thus achieved that containing the organic facies of tacrolimus.
2) compound remove impurity with active carbon: by 1) in organic facies add compound activated carbon, stir, filter, concentrate, obtain concentrated solution.
3) crystallization: by 2) in concentrated solution polar solvent, solvent resistant and water crystallization, it is thus achieved that crude tacrolimus.
As preferably, step 1) described in extraction be by the organic solvent of middle polarity, more preferably ethanol, isopropanol, acetone, most preferred ethanol.
Described extraction is to dissolve with lower member ester kind solvent, ethyl acetate, Ethyl formate, butyl acetate, more preferably ethyl acetate；Add aqueous slkali, the preferred NaOH of described aqueous slkali, KOH, K2CO3, Na2CO3, ammonia spirit；Stirring, separation, collect organic facies.
As preferably, step 2) described in compound activated carbon be 0.5～5:1 with tacrolimus weight ratio, preferably 1:2；It is stirred at room temperature 1～2h.
As preferably, step 3) described in polar solvent be ethyl acetate, acetone, ethanol, ethyl acetate, described solvent resistant is normal hexane, normal heptane, petroleum ether, diisopropyl ether, preferably normal heptane；Described polar solvent: solvent resistant: the volume ratio of water is 0.5～1.5:1～5:0.5～2.
As preferably, step 3) described in concentrated solution first dissolve with polar solvent, more described solvent resistant and water are dividedly in some parts in polar solvent, continue stirring 1h, stand overnight.
Compared with prior art, the unexpected technique effect brought is as follows for the present invention:
In prior art, extraction step is generally after macroporous adsorbent resin processes, the present invention saves resin treatment directly extracted by lixiviating solution, by the process of aqueous slkali, by a large amount of pigments, water-solubility impurity and amount of grease remove, and then obtain crude product by the way of crystallization.Relative to using macroporous resin and the purification process of silica gel column chromatography in publication, the purification process technique that the present invention provides is simply, the shortest, eluting solvent consumption greatly reduces, it is low to pollute, and is beneficial to green and produces, and simple to operate, beneficially industrialized great production.
Accompanying drawing explanation
Fig. 1 is the stereoscan photograph of the compound activated carbon of the embodiment of the present invention 1.
Fig. 2 is the graph of pore diameter distribution of the compound activated carbon of the embodiment of the present invention 1.
Fig. 3 is the HPLC spectrogram that the embodiment of the present invention 2 obtains crude tacrolimus.
Detailed description of the invention
Those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are considered as being included in the present invention.
The instrument that the present invention uses is as follows:
Detecting instrument and method:
Using FDAC S～4800 type scanning electron microscopes that the compound activated carbon of preparation is carried out sem analysis, operation voltage is 5.0kV, electric current 10 μ A, operating distance 8mm.Sample carried out surface metal spraying process, vacuum 10Pa, metal spraying time 60s before observing under vacuo.
High performance liquid chromatography (HPLC) spectral data picks up from high performance liquid chromatograph: Agilent1260；
Chromatographic column: C8 post (4.6 × 150mm, 5 μm)；
Flowing phase:
Solution A: 0.02mol/L potassium dihydrogen phosphate, adjusts pH to 3.5 with phosphoric acid.
Solution B: acetonitrile；
Ultraviolet detection wavelength: 210nm；
Column temperature: 60 DEG C；
Flow velocity: 1.0ml/min；Sample size: 20ul.
In order to be further appreciated by the present invention, below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1
The preparation method of compound activated carbon
1) wood flour screening and be dried
By moisture content be 40%, the wood flour pulverized delivered to vibrosieve screening by bucket elevator, it is thus achieved that particle diameter is the wood flour of 6～40 mesh, aerator be transported to cyclone separator, and the wood flour after separation falls as in bunker.
Wood flour is quantitatively continuously dropped into feeding screw by disk feeder below bunker, adds warm-air pipe, and at the hot-air of 120～150 DEG C, wood flour is carried out pneumatic conveying drying, and wherein hot-air flow velocity is 8 meter per seconds；Dried wood flour moisture content is 18%.
2) potassium hydroxide aqueous solution that concentration is 70% it is configured to.
3) kneading
By step 1) in dried wood flour and step 2) in knead under potassium hydroxide aqueous solution stirring condition；The weight of described wood flour and the weight ratio of potassium hydroxide aqueous solution are 1:1.
4) wood flour carbonization and activation
By step 3) in kneading after wood flour carbonization 1.0h under nitrogen protection, carbonization temperature is 280 DEG C；Then by wood flour at 800 DEG C of activation, soak time 2.0h.
5) reclaim
Wood flour after activation is washed with the hydrochloric acid solution of 45%, then cleans with the hot water of 95 DEG C.
6) centrifuge dehydration, being dried to moisture content 4～6%, last pulverizing is compound activated carbon.
Fig. 1 is the stereoscan photograph of the compound activated carbon of the present invention.As seen from the figure, the compound activated carbon of the present invention belongs to the I type of internationalization association classification, has the absorption property of excellence, and wider pore diameter range takes into account little molecule and the removal of macromolecular substances impurity.Fig. 2 is the graph of pore diameter distribution of the compound activated carbon of the present embodiment.
Embodiment 2
Taking fermentation liquid dreg 1000g, after 7L alcohol steep, it is thus achieved that concentrated solution about 60g, with diluted ethyl acetate to 500ml, add 500ml2%NaOH aqueous solution, 50 DEG C of insulations were layered to obtain ethyl acetate phase after 3 hours；Ethyl acetate mutually in add 1%NaOH aqueous solution 500ml, stand overnight after stirring.
Next day, separate to obtain extract, add the compound activated carbon that 12g is prepared by the present embodiment 1, filter after 1h is stirred at room temperature, appropriate ethyl acetate drip washing, obtain filtrate 700ml.
Concentrated filtrate, to about 40g, adds 30ml acetic acid ethyl dissolution, insulated and stirred 1h, is dividedly in some parts 40ml purified water and 160ml normal hexane in 1h, continues stirring 1h, stands overnight.
Filtering for crystallizing liquid, respectively with 40ml normal hexane and 40ml pure water, dries to obtain crude product 10g (containing FK506 about 9g), normalizing content 93%, sees Fig. 3 for 50～70 DEG C.Total recovery from dreg to crystal crude product about 78%.
Embodiment 3
1) take fermentation liquid dreg 2500g, after 20L acetone extraction, it is thus achieved that concentrated solution about 150g, be diluted to 1800ml with Ethyl formate, add 600ml1%Na2CO3Aqueous solution, 50 DEG C insulation 3 hours after be layered.
2) layering after, Ethyl formate mutually in add 600ml0.5%Na2CO3, stand overnight after stirring.
3) next day, separate to obtain extract, add the compound activated carbon that 40g is prepared by the present embodiment 1, filter after 1h is stirred at room temperature, appropriate Ethyl formate drip washing, obtain filtrate.
4) concentrated filtrate is to about 100g, adds 100ml acetone solution, 1h is stirred at room temperature, and is dividedly in some parts 50ml purified water and 500ml normal heptane in 0.5h, continues stirring 1h, stands overnight.
5) filtering for crystallizing liquid, respectively with 100ml normal heptane and 100ml pure water, dries to obtain crude product 28g (containing FK50624g), normalizing content 92.3% for 50～70 DEG C, and the total recovery from dreg to crystal crude product is 80%.
Embodiment 4
1) taking fermentation liquid dreg 2000g, after extracting with 16L isopropanol, it is thus achieved that concentrated solution about 120g, be diluted to 1200ml with butyl acetate, add 600ml0.5%KOH aqueous solution, 50 DEG C of insulations were layered after 3 hours.
2) layering after, butyl acetate mutually in add 600ml0.5%KOH aqueous solution, stand overnight after stirring.
3) next day, separate to obtain extract, add the compound activated carbon that about 50g is prepared by the present embodiment 1, filter after 2h is stirred at room temperature, appropriate butyl acetate drip washing, obtain filtrate.
4) concentrated filtrate is to about 80g, adds 50ml ethanol and dissolves, 1h is stirred at room temperature, is dividedly in some parts 200ml purified water and 300ml diisopropyl ether in 1.5h, continues stirring 1h, stands overnight.
5) filtering for crystallizing liquid, respectively with 80ml diisopropyl ether and 80ml pure water, dries to obtain crude product 22.5g (containing FK506 about 19.5g) for 50～70 DEG C, and normalizing content 91.8%, the total recovery from dreg to crystal crude product is 80.5%.
Embodiment 5
1) fermentation liquid dreg extracts concentrated solution 50L, is diluted with ethanol to 500L, adds 1.5%Na2CO3Aqueous solution 500L, 50 DEG C insulation 15 minutes after stand overnight.
2) next day, after layering, ethyl acetate mutually in add 0.5%Na2CO3Aqueous solution 500L, stands overnight after stirring.
3) the 3rd day, separate to obtain extract, add the compound activated carbon that about 10kg is prepared by the present embodiment 1, filter after 2h is stirred at room temperature, 100L ethyl acetate drip washing, obtain filtrate.
4) concentrated filtrate is to about 30L, adds 22.5L acetic acid ethyl dissolution, is stirred at room temperature, and is dividedly in some parts 30L purified water and 60L petroleum ether in 1h, continues stirring 1h, stands overnight.
5) filtering for crystallizing liquid, respectively with 30L petroleum ether and 30L pure water, dries to obtain crude product 9Kg (containing FK5067.8Kg), normalizing content 92.1%, the total recovery 78% from dreg to crystal crude product for 50～70 DEG C.
Embodiment 6: the impact that different composite type activated carbon is isolated and purified on tacrolimus
Comparative example 1,2 be respectively adopted Zhejiang activated carbon branch company of Hang Mu Industrial Co., Ltd 8815 activated carbons,
Japan's Wu Tian company egression Z activated carbon carries out isolated and purified, from the embodiment of the present invention 2 to differ only in activated carbon types different, other techniques are all identical with the embodiment of the present invention 2.The parameter of concrete acquisition crude tacrolimus is as follows:
Know from upper table, the compound activated carbon of the present invention is when purification of tacrolimus, and this pore diameter range can preferably be taken into account decolouring and remove the effect of interference crystalline impurities, has the absorption property of excellence, weight content and the crystallization yield of product, beneficially industrialized great production can be significantly improved.
The above is only the preferred embodiment of the present invention, it is noted that for those skilled in the art, under the premise of not departing from the present invention, it is also possible to make some improvement, and these improvement also should be regarded as protection scope of the present invention.
Claims (10)
1. a compound activated carbon, it is characterised in that the specific surface area of described compound activated carbon is 800～1000m2/ g, aperture is 2.0～8.0nm, and the volume in hole is 0.5～1.0cm3/g。
The preparation method of compound activated carbon the most as claimed in claim 1, comprises the steps:
1) wood flour screening and be dried
Filtering out the wood flour that particle diameter is 6～40 mesh, at the hot-air of 120～150 DEG C, wood flour is carried out pneumatic conveying drying, dried wood flour moisture content is 15～20%；Described hot-air flow velocity is 6～10 meter per seconds, preferably 8 meter per seconds；
2) compound concentration is the alkaline aqueous solution of 65～75%；
3) kneading
By step 1) in dried wood flour and step 2) knead under neutral and alkali aqueous solution stirring condition；The weight of described wood flour and the weight ratio of alkaline aqueous solution are 0.8～1.2:1, preferably 1:1；
4) wood flour carbonization and activation
By step 3) in kneading after wood flour carbonization 0.5～1.5h, preferably 1.0h under nitrogen protection, carbonization temperature is 250～300 DEG C, preferably 280 DEG C；Then by wood flour at 700～900 DEG C, preferably 800 DEG C activation, soak time 2.0h；
5) reclaim
By wood flour after activation with 40～the hydrochloric acid solution washing of 50%, then clean with the hot water of 90～100 DEG C；
6) centrifuge dehydration, being dried to moisture content 4～6%, last pulverizing is compound activated carbon.
3. preparation method as claimed in claim 2, it is characterised in that step 1) described in wood flour to be dried front moisture content be 40%；Step 2) described in alkaline aqueous solution be sodium hydroxide, potassium hydroxide aqueous solution.
The compound activated carbon the most as claimed in claim 1 application in purification of tacrolimus.
5. as according to any one of claims 1 to 3, compound activated carbon, for the method for purification of tacrolimus, comprises the steps:
1) fermentation liquor pretreatment: first by tacrolimus filtering fermentation liquor, extract, extract, wash after, it is thus achieved that containing the organic facies of tacrolimus；
2) compound remove impurity with active carbon: by 1) in organic facies add compound activated carbon, stir, filter, concentrate, obtain concentrated solution；
3) crystallization: by 2) in concentrated solution polar solvent, solvent resistant and water crystallization, it is thus achieved that crude tacrolimus.
6. method as claimed in claim 5, it is characterised in that step 1) in
Described extraction is with the organic solvent of middle polarity, preferred alcohol, isopropanol, acetone, more preferably ethanol；
Described extraction is to dissolve with lower member ester kind solvent, ethyl acetate, Ethyl formate, butyl acetate, more preferably ethyl acetate；Add aqueous slkali, the preferred NaOH of described aqueous slkali, KOH, K2CO3, Na2CO3, ammonia spirit；Stirring, separation, collect organic facies.
7. method as claimed in claim 6, it is characterised in that described aqueous slkali is 1:1～3, preferably 1:1 with the volume ratio of organic facies.
8. method as claimed in claim 5, it is characterised in that step 2) described in compound activated carbon be 0.5～5:1 with tacrolimus weight ratio, preferably 1:2；It is stirred at room temperature 1～2h.
9. method as claimed in claim 5, it is characterised in that step 3) described in polar solvent be ethyl acetate, acetone, ethanol, ethyl acetate, described solvent resistant is normal hexane, normal heptane, petroleum ether, diisopropyl ether；Described polar solvent: solvent resistant: the volume ratio of water is 0.5～1.5:1～5:0.5～2.
10. the method as described in claim 5 or 9, it is characterised in that step 3) described in concentrated solution first dissolve with polar solvent, more described solvent resistant and water are dividedly in some parts in polar solvent, continue stirring 1h, stand overnight.
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| CN201610172215.0A CN105819444A (en) | 2016-03-24 | 2016-03-24 | Composite type activated carbon and application thereof in purifying tacrolimus |
| CN202010262935.2A CN111547718A (en) | 2016-03-24 | 2016-03-24 | Composite activated carbon and application thereof in purifying tacrolimus |
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| CN108929335A (en) * | 2018-08-31 | 2018-12-04 | 福建省微生物研究所 | A kind of preparation method of tacrolimus coarse-grain |
| CN112390817A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Method for extracting tacrolimus fermentation liquor by salting out |
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| CN101423210A (en) * | 2008-10-20 | 2009-05-06 | 浙江富来森竹炭有限公司 | Method for preparing active carbon for polar electric pole by using biomass material as raw material |
| CN102304105A (en) * | 2011-07-15 | 2012-01-04 | 鲁南新时代生物技术有限公司 | Method for preparing high-purity Orlistat |
| CN104445190A (en) * | 2013-09-13 | 2015-03-25 | 中国科学院兰州化学物理研究所 | Method for preparation of activated carbon with high specific surface area by using asparagus lettuce leaf as carbon source |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108929335A (en) * | 2018-08-31 | 2018-12-04 | 福建省微生物研究所 | A kind of preparation method of tacrolimus coarse-grain |
| CN112390817A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Method for extracting tacrolimus fermentation liquor by salting out |
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