CN108017530B - Method for continuously separating coenzyme Q10 from mushroom dregs - Google Patents
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Abstract
The invention discloses a method for continuously separating coenzyme Q10 from mushroom dregs, which comprises the following steps: (1) dissolving a crude extract of coenzyme Q10 in a nonpolar organic solvent to prepare a feed solution; (2) continuously introducing a feed liquid and an eluent into the simulated moving bed chromatographic system, and continuously collecting raffinate from a raffinate port of the simulated moving bed chromatographic system; (3) and (3) concentrating the raffinate obtained in the step (2) under reduced pressure, dissolving again, and crystallizing, filtering and drying to obtain a refined coenzyme Q10 product with the purity of more than 98%. The method has the characteristics of high yield, high recovery rate, low solvent consumption and continuous production, and is suitable for industrial large-scale popularization and application.
Description
Technical Field
The invention belongs to the technical field of chemical separation, and particularly relates to a method for continuously separating coenzyme Q10 from mushroom dregs.
Background
Coenzyme Q10, also called ubiquinone, is a fat-soluble quinone compound, mainly exists in heart, liver and kidney cells of animals, has a chemical name of 2- (3,7,11,15,19,23,27,31,35, 39-decamethyl-2, 6,10,14,18,22,26,30,34, 38-forty decenyl) -5, 6-dimethoxy-3-methyl-p-benzoquinone, and a molecular formula of C-tetrafluoquinone59H90O4Molecular weight 863.34. Coenzyme Q10 has important physiological functions of scavenging free radicals, improving intracellular respiration, enhancing immunity and the like, has continuously expanded market demand, and is widely applied to the fields of medicines, cosmetics, food additives and the like.
The production method of the coenzyme Q10 mainly comprises a chemical synthesis method, an animal and plant cell culture method and a microbial fermentation method, wherein the microbial fermentation method has the advantages of high process stability, easiness in large-scale production, simplicity in operation, high biological activity of products, easiness in absorption and the like, and is a research hotspot for the production of the coenzyme Q10 at present. The fermentation liquor prepared by the microbial fermentation method is centrifuged, filtered, freeze-dried and crushed to obtain bacterial dregs, a coenzyme Q10 crude extract is obtained by extraction, and a high-purity coenzyme Q10 product is obtained by further purification treatment. The existing extraction method comprises a solvent extraction method, a saponification method and a supercritical fluid extraction method, and then the crude product of the coenzyme Q10 is further purified by combining the technologies of silica gel column chromatography, recrystallization and the like. However, the crude extract of coenzyme Q10 mainly contains coenzyme Q analogues with different numbers of isopentene units on side chains, and the separation difficulty is higher.
CN103819326A discloses a method for refining coenzyme Q10 by ultrasonic crushing, organic solvent extraction, silica gel column chromatography and crystallization in turn. CN101429108A discloses a method for purifying coenzyme Q10 by sequentially extracting with absolute ethyl alcohol, water and n-hexane, performing silica gel column chromatography and crystallizing. CN102391092A discloses a method for extracting mushroom dregs by supercritical carbon dioxide, and then obtaining coenzyme Q10 with the purity of more than 99.5 percent by silica gel column chromatography and crystallization. CN101987815A discloses a method for preparing coenzyme Q10 with purity of more than 98% by combining adsorption resin and silica gel column chromatography. These methods all require silica gel column chromatography, and although high-purity coenzyme Q10 can be obtained, the above methods are all batch operation processes, and have problems of large organic solvent usage, small preparation amount, low silica gel utilization rate and the like, so that the process is not economical.
The simulated moving bed chromatography is a preparative chromatography technology with the most industrialized prospect at present, and four inlets and outlets, such as an eluent inlet, a feeding liquid inlet, an extract liquid outlet, a raffinate liquid outlet and the like, divide all chromatographic columns into four regions with different flow rates and respectively undertake different functions. The device simulates the countercurrent movement of an eluent and a stationary phase by timing switching of four inlet and outlet materials, thereby realizing the continuity of feeding and discharging. The mixed solution containing the strongly adsorbed component and the eluent is continuously collected at the extract outlet, and the mixed solution containing the weakly adsorbed component and the eluent is continuously collected at the raffinate outlet. On the one hand, this operation allows continuous feeding and therefore high productivity; on the other hand, the eluent is recycled, so that the consumption of the solvent is less, and the cost of large-scale preparation can be reduced. The target component with high purity can be obtained by designing appropriate flow rates for each zone.
Disclosure of Invention
Aiming at the defects of the method, the invention provides the method for continuously separating the coenzyme Q10 from the mushroom dregs, and the method has the advantages of simple process, large product preparation amount, high purity, less solvent consumption and low production cost.
The method separates coenzyme Q10 from the mushroom dregs by a simulated moving bed chromatography and crystallization combined method, the method takes a filler with a surface rich in polar groups as a stationary phase, adjusts the type and the proportion of an eluent, designs proper flow rate and switching time of each area, can realize continuous separation of coenzyme Q10 and impurities by adopting the simulated moving bed chromatography, and then crystallizes and purifies the coenzyme Q10 obtained by separation.
A method for continuously separating coenzyme Q10 from mushroom dregs comprises the following steps:
(1) dissolving a crude extract of coenzyme Q10 in a nonpolar organic solvent to prepare a feed solution;
(2) continuously introducing a feed liquid and an eluent into the simulated moving bed chromatographic system, and continuously collecting raffinate from a raffinate port of the simulated moving bed chromatographic system;
the simulated moving bed chromatographic system consists of 4-32 chromatographic columns filled with a fixed phase, and comprises four zones, wherein each zone is formed by connecting 1-8 chromatographic columns in series. The zones can be connected in series or disconnected, and an isocratic operation mode or a gradient operation mode can be adopted. Presetting operation parameters such as flow, switching time, switching times, column temperature and the like of each area, continuously pumping the feed liquid and the eluent, and continuously collecting raffinate rich in coenzyme Q10 from a raffinate port after the system reaches a steady state.
Before a simulated moving bed chromatographic system operates, a wet column packing method is adopted to pack stationary phase particles into a chromatographic column, a column packing solvent is n-hexane or petroleum ether, symmetry experiments are carried out on the pressure, the column efficiency, the solute retention time, the separation degree and the total porosity of each column, and the performance indexes of each chromatographic column are ensured to be consistent. The separable zones were preliminarily determined according to "trigonometric theory", and the flow rates and switching times of the zones were adjusted until complete separation of coenzyme Q10 from the impurities was achieved.
(3) Concentrating the raffinate obtained in the step (2) to remove the solvent, adding an organic solvent at 20-60 ℃ until the solid is just dissolved, cooling to-5 ℃, cooling and crystallizing for 12-36 hours, filtering, washing a filter cake with water, and drying in vacuum at 20-40 ℃ to obtain a refined coenzyme Q10 product with the purity of more than 98%.
The crude extract of coenzyme Q10 in the step (1) is extracted from the mushroom dregs obtained by microbial fermentation, specifically, the method described in the patent application with the publication number of CN101314782A, CN101619330A or CN105886562A can be referred to culture the strain, and the fermented liquid is filtered, dried and crushed to obtain the mushroom dregs; the extraction method for extracting coenzyme Q10 crude extract from mushroom residue is percolation extraction, organic solvent extraction, alcohol-base saponification or supercritical fluid extraction, and can be specifically disclosed in patent application CN106146278A, CN101381747A, CN102391092A or CN 104694613A.
The nonpolar organic solvent is one or a mixture of any two of n-hexane, cyclohexane, n-heptane, n-octane and petroleum ether. These hydrophobic organic solvents have a higher solubility for the crude coenzyme Q10 extract.
The total concentration of the feeding liquid is 5-500 g/L, and the total concentration is preferably 50-300 g/L. If the feed concentration is too low, the production capacity is reduced and the process economy is reduced; if the feeding concentration is too high, the complete separation area is obviously reduced, the difficulty of designing the operation conditions is increased, and the separation difficulty is increased.
The stationary phase of the simulated moving bed chromatographic system is polar macroporous adsorption resin, ion exchange resin, silica gel or alumina. The stationary phases are rich in polar groups such as hydroxyl groups and the like, can form hydrogen bonds with carbon groups in coenzyme Q class analogs, and identify the micro structural difference between the analogs according to the difference of the acting force of the hydrogen bonds.
The stationary phase is spherical particles with uniform particle size, uniform pore diameter and high mechanical strength.
The particle size of the stationary phase is controlled to be 5-200 μm, and more preferably 10-100 μm. If the particle size is too large, the column efficiency is reduced, which is not beneficial to the separation of coenzyme Q10 and impurities; if the particle size is too small, the column pressure is too high, which is not favorable for operation.
The aperture of the stationary phase is controlled to be 5-100 nm, and the preferred aperture is 10-50 nm. If the aperture of the filler is too small, the coenzyme Q10 molecules are not easy to enter the inside of the pore channel, so that the separation effect is reduced; if the pore diameter of the filler is too large, the diffusion in the pores is slow, and the mass transfer resistance is large.
The eluent is one or a mixture of any two of N-hexane, cyclohexane, N-heptane, N-octane, petroleum ether, acetonitrile, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide and monohydric alcohol with the carbon atom number of 1-4. Further preferred eluents are mixtures of n-hexane and ethyl acetate.
Preferably, the volume percentage of the ethyl acetate in the eluent is 1-20%. If the proportion of the ethyl acetate is too high, the polarity of the mobile phase is strong, and the separation degree of the coenzyme Q10 and impurities is poor; if the proportion of ethyl acetate is too low, the polarity of the mobile phase is weak, the retention time of the coenzyme Q10 in the system is too long, and the system is difficult to stabilize.
The size of the chromatographic column of the simulated moving bed chromatographic system is 5-500 mm in diameter and 50-1000 mm in length, and the preferred size is 10-100 mm in diameter and 100-500 mm in length. If the size of the chromatographic column is too small, the production capacity is low; if the size of the chromatographic column is too large, the packing is difficult to fill, the wall effect is obvious, and the separation capability of the chromatographic column is reduced.
The operation parameters of the simulated moving bed chromatographic system are controlled as follows: the flow rate of the eluent is 1-1000 mL/min, the flow rate of the feeding liquid is 1-100 mL/min, the flow rate of the extraction liquid is 1-100 mL/min, the flow rate of the raffinate is 1-100 mL/min, and the switching time is 1-50 min. The switching time is further preferably 3-10 min, and if the switching time is too short, the switching valve is easy to damage; if the switching time is too long, the system is difficult to reach steady state.
The separation temperature of the simulated moving bed chromatographic system is 0-60 ℃, and the preferable temperature is 20-50 ℃. If the temperature is too low, the solubility of the coenzyme Q10 in the solvent is obviously reduced, and the concentration of the feeding liquid is limited; if the temperature is too high, coenzyme Q10 is easily oxidized and deteriorated during the separation process.
The organic solvent is one or a mixture of any two of monohydric alcohol with 1-4 carbon atoms, acetonitrile, acetone, ethyl acetate, n-hexane and n-heptane.
The volume-mass ratio of the added amount of the organic solvent to the solid obtained after the concentration of the raffinate is 20-80L/kg.
Compared with the prior art, the invention has the following advantages:
1. the continuous chromatographic technique is adopted, so that the utilization rate of the stationary phase is improved, and the consumption of the stationary phase is reduced.
2. The continuous production of the coenzyme Q10 is realized, the production process is full-automatic, the labor intensity is low, and the production cost is low.
3. The purity of the coenzyme Q10 obtained by the purification method of the invention reaches more than 98%, the yield is high, the solvent consumption is low, and the method is suitable for large-scale popularization and application.
Drawings
FIG. 1 is a liquid chromatogram of a coenzyme Q10 product obtained in example 1 of the present invention.
Detailed Description
In order to further understand the present invention, the following will specifically describe a method for continuously separating coenzyme Q10 from mushroom dregs, which is provided by the present invention, with reference to the following examples, but the present invention is not limited to these examples, and the insubstantial modifications and adaptations made by those skilled in the art under the core teaching of the present invention still fall within the scope of the present invention.
The following examples of simulated moving bed devices using German CESP C9116 (Noll, Germany) equipped with a multiport rotary valve, which can be connected to 16 chromatographic columns at most, each zone of chromatographic columns of the same number, in 1~4 changes; the device is provided with 4S-100 liquid phase pumps, wherein the flow rate of a feed pump is 0-10 mL/min, and the flow rates of an eluent pump, an extraction liquid pump and an extraction raffinate pump are 0-50 mL/min. Eluent is injected between zone 4 and zone 1, feed solution is injected between zone 2 and zone 3, coenzyme Q10 is collected at the raffinate outlet between zone 3 and zone 4, and impurity 10 is collected at the extract outlet between zone 1 and zone 2. At each switching time (note: this switching time is adjustable), the column switches one position in the opposite direction of the eluent flow.
In the following embodiments of the invention, the determination of the coenzyme Q10 content is performed according to the method described in Chinese pharmacopoeia, and the analysis conditions of the liquid chromatography are as follows: waters Atlantis T3 analytical column (250mm × 4.6mm,5 μm), methanol-absolute ethanol (1:1) as mobile phase, flow rate 1mL/min, sample amount 20 μ L, ultraviolet detector as detector, and detection wavelength 275 nm.
The method for calculating the purity of the coenzyme Q10 comprises the following steps: a small amount of the collected coenzyme Q10 product was dissolved in absolute ethanol and diluted to prepare a solution containing about 0.2mg of coenzyme Q10 per 1mL, and the purity was calculated as the peak area by an external standard method.
The calculation method of the purity and the recovery rate of the invention is as follows:
purity ═ the mass of coenzyme Q10 in the product ÷ the total mass of the product × 100%
The recovery rate is the mass of coenzyme Q10 in the product ÷ the mass of coenzyme Q10 in the starting material × 100%.
Example 1
Dissolving crude extract of coenzyme Q10 in n-hexane to obtain feed solution with solid concentration of 50g/L, wherein the content of coenzyme Q10 is about 62.3%.
The simulated moving bed is provided with 8 chromatographic columns, and the size is 1cm multiplied by 25 cm; the stationary phase is silica gel with the particle size of 45 mu m and the aperture of 10 nm; the eluent is a mixture of normal hexane and ethyl acetate, wherein the volume percentage of the ethyl acetate is 10%; the operation temperature is 30 ℃; the operating parameters are optimally determined as: eluent flow rate of 16mL/min, feed flow rate of 2mL/min, extract flow rate of 9.5mL/min, raffinate flow rate of 8.5mL/min, and switching time of 5 min. After 32 consecutive switches, the system reached equilibrium and a coenzyme Q10 rich solution was collected from the raffinate outlet. Analysis showed that the coenzyme Q10 content of the raffinate was 95.6%.
Concentrating the raffinate into solid, adding ethanol at 50 ℃ until the ethanol is completely dissolved, wherein the solid-liquid ratio is 1:50, gradually reducing the temperature to 5 ℃, cooling and crystallizing for 24h, filtering, and drying in a vacuum drying oven at 30 ℃ for 24h to obtain a refined coenzyme Q10 product. The purity of the coenzyme Q10 product is 99.2% by liquid chromatography analysis, and the recovery rate of the whole process is 95.5%.
Example 2
Dissolving crude extract of coenzyme Q10 in n-hexane to obtain feed solution with solid concentration of 100g/L, wherein the content of coenzyme Q10 is about 68.7%.
The simulated moving bed is provided with 8 chromatographic columns, and the size is 1cm multiplied by 25 cm; the stationary phase is silica gel with the particle size of 20 mu m and the pore diameter of 22 nm; the eluent is a mixture of normal hexane and ethanol, wherein the volume percentage of the ethanol is 5%; the operation temperature is 30 ℃; the operating parameters are optimally determined as: eluent flow rate of 15.4mL/min, feed flow rate of 1.5mL/min, extract flow rate of 8.9mL/min, raffinate flow rate of 8.0mL/min, and switching time of 4 min. After 32 consecutive switches, the system reached equilibrium and a coenzyme Q10 rich solution was collected from the raffinate outlet. Analysis showed that the coenzyme Q10 content of the raffinate was 96.5%.
Concentrating the raffinate into solid, adding ethyl acetate at 30 ℃ until the raffinate is completely dissolved, wherein the solid-liquid ratio is 1:20, gradually reducing the temperature to 0 ℃, cooling, crystallizing for 24 hours, filtering, and drying in a vacuum drying oven at 30 ℃ for 24 hours to obtain a refined coenzyme Q10 product. The purity of the coenzyme Q10 product is 99.2% by liquid chromatography analysis, and the recovery rate of the whole process is 95.9%.
Example 3
Dissolving crude extract of coenzyme Q10 in n-hexane to obtain feed solution with solid concentration of 80g/L, wherein the content of coenzyme Q10 is about 70.3%.
The simulated moving bed is provided with 16 chromatographic columns, and the size is 1cm multiplied by 15 cm; the stationary phase is neutral alumina with 200-300 meshes; the eluent is a mixture of normal hexane and ethyl acetate, wherein the volume percentage of the ethyl acetate is 10%; the operation temperature is 40 ℃; the operating parameters are optimally determined as: eluent flow rate of 3mL/min, feed flow rate of 1.5mL/min, extract flow rate of 2.2mL/min, raffinate flow rate of 2.3mL/min, and switching time of 10 min. After 48 consecutive switching, the system reached equilibrium and a coenzyme Q10 rich solution was collected from the raffinate outlet. Analysis showed that the coenzyme Q10 content of the raffinate was 95.2%.
Concentrating the raffinate into solid, adding ethanol at 50 ℃ until the ethanol is completely dissolved, wherein the solid-liquid ratio is 1:50, gradually reducing the temperature to 5 ℃, cooling, crystallizing for 12h, filtering, and drying in a vacuum drying oven at 35 ℃ for 12h to obtain a refined coenzyme Q10 product. The purity of the coenzyme Q10 product is 98.2% by liquid chromatography analysis, and the recovery rate of the whole process is 94.5%.
Example 4
The crude extract of coenzyme Q10 was dissolved in cyclohexane to prepare a feed solution with a solid concentration of 150g/L, wherein the coenzyme Q10 content was about 72.7%.
The simulated moving bed is provided with 16 chromatographic columns, and the size is 1cm multiplied by 15 cm; the stationary phase is neutral alumina with 200-300 meshes; the eluent is a mixture of cyclohexane and methanol, wherein the volume percentage of the methanol is 5%; the operation temperature is 20 ℃; the operating parameters are optimally determined as: eluent flow rate of 7mL/min, feed flow rate of 2mL/min, extract flow rate of 4.8mL/min, raffinate flow rate of 4.2mL/min, and switching time of 5 min. After 48 consecutive switching, the system reached equilibrium and a coenzyme Q10 rich solution was collected from the raffinate outlet. Analysis showed that the coenzyme Q10 content of the raffinate was 95.0%.
Concentrating the raffinate into solid, adding acetone at 30 ℃ until the acetone is completely dissolved, wherein the solid-liquid ratio is 1:20, gradually reducing the temperature to 5 ℃, cooling and crystallizing for 24h, filtering, and drying in a vacuum drying oven at 35 ℃ for 12h to obtain a refined coenzyme Q10 product. The purity of the coenzyme Q10 product is 98.0% by liquid chromatography analysis, and the recovery rate of the whole process is 93.8%.
Claims (5)
1. A method for continuously separating coenzyme Q10 from mushroom dregs comprises the following steps:
(1) dissolving a crude extract of coenzyme Q10 in a nonpolar organic solvent to prepare a feed solution; the total concentration of the feeding liquid is 5-500 g/L;
(2) continuously introducing a feed liquid and an eluent into the simulated moving bed chromatographic system, and continuously collecting raffinate from a raffinate port of the simulated moving bed chromatographic system; the operation parameters of the simulated moving bed chromatographic system are controlled as follows: the separation temperature is 0-60 ℃, the flow rate of an eluent is 1-1000 mL/min, the flow rate of a feeding liquid is 1-100 mL/min, the flow rate of an extraction liquid is 1-100 mL/min, the flow rate of a raffinate is 1-100 mL/min, and the switching time is 1-50 min;
the simulated moving bed chromatographic system consists of 4-32 chromatographic columns filled with a fixed phase, and comprises four zones, wherein each zone is formed by connecting 1-8 chromatographic columns in series;
the size of a chromatographic column of the simulated moving bed chromatographic system is 10-100 mm in diameter and 100-500 mm in length;
the stationary phase of the simulated moving bed chromatographic system is silica gel or alumina, the particle size of the stationary phase is controlled to be 10-100 mu m, and the pore diameter is controlled to be 10-50 nm;
(3) concentrating the raffinate obtained in the step (2) to remove the solvent, adding an organic solvent to dissolve at the temperature of 20-60 ℃, cooling and crystallizing at the temperature of-5 ℃ for 12-36 h, filtering, washing a filter cake with water, and drying in vacuum at the temperature of 20-40 ℃ to obtain a refined coenzyme Q10 product with the purity of more than 98%;
the volume-mass ratio of the added amount of the organic solvent to the solid obtained after the concentration of the raffinate is 20-80L/kg.
2. The method for continuously separating the coenzyme Q10 from the mushroom dregs according to claim 1, wherein the nonpolar organic solvent is one or a mixture of any two of n-hexane, cyclohexane, n-heptane, n-octane and petroleum ether.
3. The method for continuously separating the coenzyme Q10 from the mushroom dregs according to claim 1, wherein the eluent is one or a mixture of any two of N-hexane, cyclohexane, N-heptane, N-octane, petroleum ether, acetonitrile, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide and monohydric alcohol with 1-4 carbon atoms.
4. The method for continuously separating the coenzyme Q10 from the mushroom dregs according to claim 3, wherein the eluent is a mixture of n-hexane and ethyl acetate, and the volume percentage of the ethyl acetate is 1-20%.
5. The method for continuously separating the coenzyme Q10 from the mushroom dregs according to claim 1, wherein in the step (3), the organic solvent is one or a mixture of any two of monohydric alcohol with 1-4 carbon atoms, acetonitrile, acetone, ethyl acetate, n-hexane and n-heptane.
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| CN110465114B (en) * | 2019-08-23 | 2021-08-20 | 内蒙古金达威药业有限公司 | Simulated moving bed continuous chromatography chromatographic system, application thereof and method for purifying coenzyme Q10 |
| CN112920035A (en) * | 2019-12-06 | 2021-06-08 | 中国科学院大连化学物理研究所 | Method for removing Q11 impurity in coenzyme Q10 by using preparation chromatography |
| CN115677468A (en) * | 2022-11-02 | 2023-02-03 | 广东润和生物科技有限公司 | Method for purifying coenzyme Q10 |
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| CN101233095A (en) * | 2005-06-10 | 2008-07-30 | 协和发酵工业株式会社 | Method of purifying ubiquinone-10 |
| CN101987815A (en) * | 2010-09-28 | 2011-03-23 | 华东理工大学 | Purification process for preparing high-purity coenzyme Q10 |
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| CN101987815A (en) * | 2010-09-28 | 2011-03-23 | 华东理工大学 | Purification process for preparing high-purity coenzyme Q10 |
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