CN117142973B - Levodopa and separation and purification method thereof - Google Patents
Levodopa and separation and purification method thereof Download PDFInfo
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- CN117142973B CN117142973B CN202311438767.8A CN202311438767A CN117142973B CN 117142973 B CN117142973 B CN 117142973B CN 202311438767 A CN202311438767 A CN 202311438767A CN 117142973 B CN117142973 B CN 117142973B
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- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims abstract description 93
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 229960004502 levodopa Drugs 0.000 title claims abstract description 89
- 238000000034 method Methods 0.000 title claims abstract description 49
- 238000000746 purification Methods 0.000 title abstract description 14
- 238000000926 separation method Methods 0.000 title abstract description 14
- 238000013375 chromatographic separation Methods 0.000 claims abstract description 80
- 239000011550 stock solution Substances 0.000 claims abstract description 46
- 239000011347 resin Substances 0.000 claims abstract description 29
- 229920005989 resin Polymers 0.000 claims abstract description 29
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 20
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001179 sorption measurement Methods 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 8
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 4
- 238000004132 cross linking Methods 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 36
- 239000003480 eluent Substances 0.000 claims description 32
- 239000002994 raw material Substances 0.000 claims description 31
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 16
- 238000000855 fermentation Methods 0.000 claims description 11
- 230000004151 fermentation Effects 0.000 claims description 11
- 230000000813 microbial effect Effects 0.000 claims description 9
- 235000010323 ascorbic acid Nutrition 0.000 claims description 8
- 229960005070 ascorbic acid Drugs 0.000 claims description 8
- 239000011668 ascorbic acid Substances 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 abstract description 8
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 abstract description 8
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 abstract description 6
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 229940107700 pyruvic acid Drugs 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000007599 discharging Methods 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004042 decolorization Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- 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
- B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
- B01D15/18—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns
- B01D15/1814—Recycling of the fraction to be distributed
- B01D15/1821—Simulated moving beds
- B01D15/185—Simulated moving beds characterised by the components to be separated
-
- 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
- B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
- B01D15/18—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns
- B01D15/1864—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns using two or more columns
- B01D15/1871—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns using two or more columns placed in series
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Sustainable Development (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention relates to the technical field of separation and purification, and discloses levodopa and a separation and purification method thereof, wherein the levodopa is obtained by the following steps: taking the raw liquid of the levodopa, and carrying out chromatographic separation in a simulated moving bed chromatographic separation system to obtain raffinate, namely the levodopa; wherein the simulated moving bed chromatographic separation system adopts a chromatographic column filled with nonpolar macroporous adsorption resin, the nonpolar macroporous adsorption resin is mainly formed by cross-linking polymerization of styrene and divinylbenzene, and the adding ratio of the divinylbenzene to the styrene is (0.45-0.75): 1. The separation and purification method has good effect of removing impurities such as tyrosine, catechol, pyruvic acid and the like in the levodopa stock solution, and can improve the yield and purity of the levodopa.
Description
Technical Field
The invention relates to the technical field of separation and purification, in particular to levodopa and a separation and purification method thereof.
Background
Levodopa, an organic compound, also known as 3, 4-dihydroxyphenylalanine, is readily soluble in dilute hydrochloric acid and formic acid, and is practically insoluble in ethanol, benzene and chloroform. In medicine, the levodopa is mainly used for treating parkinsonism, hepatic encephalopathy, neuralgia, and promoting the growth and development of children.
The preparation method of L-dopa comprises chemical method, enzyme catalysis synthesis method, microorganism fermentation method and plant extraction method. In order to achieve the quality level of the raw materials, various preparation methods generally need to be refined and purified after synthesizing or extracting the levodopa.
In the prior art, various methods for refining and purifying the levodopa have the best purity of the Chinese patent with the application number of 201710711008.2, the purity of 99.8 percent, however, the purity of the product has a certain gap with the requirements of United states pharmacopoeia, and the yield is not very high and is 88 to 91 percent.
Disclosure of Invention
The invention aims to provide a levodopa and a separation and purification method thereof, which utilize a simulated moving bed chromatographic separation system to carry out chromatographic separation so as to solve the technical problems of lower purity and lower product yield of the levodopa in the prior art.
The invention provides a method for separating and purifying levodopa, which comprises the steps of taking a levodopa stock solution, and carrying out chromatographic separation in a simulated moving bed chromatographic separation system to obtain raffinate, namely the levodopa;
wherein the simulated moving bed chromatographic separation system adopts a chromatographic column filled with nonpolar macroporous adsorption resin, the nonpolar macroporous adsorption resin is mainly formed by cross-linking polymerization of styrene and divinylbenzene, and the adding ratio of the divinylbenzene to the styrene is (0.45-0.75): 1.
Further, the chromatographic separation in the simulated moving bed chromatographic separation system specifically comprises:
step 1: the method comprises the steps of (1) carrying out self-circulation of feed liquid in a chromatographic column in a simulated moving bed chromatographic separation system, and separating raw materials injected into the system;
step 2: enabling the eluent to enter a simulated moving bed chromatographic separation system, pushing the band to move in the system, thereby achieving the effect of continuously separating components in the column body and simultaneously flowing out raffinate;
step 3: enabling the eluent and the levodopa stock solution to respectively enter different positions of a simulated moving bed chromatographic separation system at the same time, and enabling the extracting solution and the raffinate to flow out from different outlets;
repeating the steps 1-3, and continuously separating out an extracting solution and a raffinate, wherein the raffinate is the levodopa.
Further, in the step 1, the chromatographic column is self-circulated until the volume of the feed liquid accumulated in the circulation pipeline of the simulated moving bed chromatographic separation system reaches 0.8-1.0BV.
Further, the chromatographic separation temperature is 20-30 ℃.
Further, the levodopa stock solution is produced by a microbial fermentation method, decolorized and filtered stock solution, the concentration of the stock solution is 30g/L, and ascorbic acid is added to prevent oxidation, and the pH value of the stock solution is 1-3.
Further, the eluent is deionized water.
Further, the volume ratio of the eluent to the levodopa stock solution is (4.5-5.0): 1.
Further, the simulated moving bed chromatographic separation system comprises 6 chromatographic columns, and the 6 chromatographic columns are sequentially connected in series from head to tail.
Further, the flow rate of the eluent is 8-10L/h, and the feeding flow rate of the levodopa stock solution is 8-10L/h.
The invention also discloses the levodopa which is obtained by the method for separating and purifying the levodopa.
Compared with the prior art, the invention has the beneficial effects that:
the method for separating and purifying the levodopa has good effect of removing impurities such as tyrosine, catechol, pyruvic acid and the like in the raw solution of the levodopa, and can improve the yield and purity of the levodopa, thereby improving the quality of finished products of the levodopa, reducing the energy consumption of unit products for producing the levodopa, and ensuring that the yield of the levodopa in the obtained raffinate reaches more than 99 percent, the purity of the levodopa reaches more than 99.85 percent and meets the quality requirement of European Pharmacopoeia (EP) of United States Pharmacopoeia (USP).
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of a simulated moving bed chromatographic separation system according to the present invention.
Wherein, 1, a raw material pump; 2. a water pump; 31. a first chromatographic column; 32. a second chromatographic column; 33. a third chromatographic column; 34. a fourth chromatographic column; 35. a fifth chromatographic column; 36. a sixth chromatographic column; 41. a first circulation pump; 42. a second circulation pump; 43. a third circulation pump; 44. a fourth circulation pump; 45. a fifth circulation pump; 46. a sixth circulation pump; 5. an extract tank; 6. a residual liquid tank; 7. automatic valve opening and closing of raw materials; 8. the water automatically opens and closes the valve; 9. the extracting solution automatically opens and closes the valve; 10. the raffinate automatically switches on and off the valve; 11. a first mass flow meter; 12. a second mass flow meter; 13. a third mass flow meter; 14. an extracting solution self-control regulating valve; 15. a raffinate self-control regulating valve; 16. a column top pressure gauge; 17. a column bottom pressure gauge; 18. and (3) circulating the automatic switching valve.
Detailed Description
The following description of the embodiments of the present invention will be made apparent and fully in view of the accompanying drawings, in which some, but not all embodiments of the invention are shown.
The components of the embodiments of the present invention generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations. Thus, the following detailed description of the embodiments of the invention, as presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention.
All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Different from the prior art that the operation such as repeated crystallization is adopted for purifying the levodopa stock solution, the embodiment of the invention provides a method for separating and purifying the levodopa, the levodopa stock solution is taken and is subjected to chromatographic separation in a simulated moving bed chromatographic separation system, the obtained raffinate is the levodopa, the extraction rate of the levodopa can reach more than 99 percent in a chromatographic separation mode, the purity reaches more than 99.85 percent, and the quality of a finished product of the levodopa is obviously improved.
The levodopa stock solution is produced by a microbial fermentation method, and is decolorized and filtered, wherein the concentration of the stock solution is 30g/L, ascorbic acid is added to prevent oxidation, the pH value of the stock solution is 1-3, the decolorization is generally performed by an activated carbon decolorization method, the adding proportion of the ascorbic acid is required to be determined according to the storage time, and the addition of 300-1000g of an aqueous solution of the ascorbic acid is generally kept in 50L of materials.
Whereas the simulated moving bed chromatographic separation system is a conventional apparatus in the art for achieving industrialization and continuity of chromatographic separation, in one embodiment, as shown in FIG. 1, the simulated moving bed chromatographic separation system comprises:
a raw material pump 1, an inlet of which is connected with a raw material supply pipe;
the inlet of the water pump 2 is connected with a water supply pipeline;
the top end of the chromatographic column is connected with the outlet of the raw material pump 1 and the outlet of the water pump 2 through pipelines;
the inlet of the chromatographic circulating pump is connected with the bottom end of the chromatographic column through a circulating pipeline, and the outlet of the chromatographic circulating pump is connected with the top end of the next chromatographic column through a circulating pipeline;
an extract tank 5, wherein the extract tank 5 is connected with an outlet of the chromatographic circulating pump through a pipeline;
and the raffinate tank 6 is connected with the outlet of the chromatographic circulating pump through a pipeline.
The simulated moving bed chromatographic separation column can use 4, 5, 6, 8 and 10, if 4 and 5 are used, the separation cannot be thoroughly performed because of the chemical structure properties of the levodopa and the tyrosine. If 8 or 10 chromatographic columns are used in industrial production, the production and construction costs are increased due to the investment of equipment and resin. Therefore, in order to simultaneously consider the energy consumption and the product purity of the separation and purification of the levodopa, the number of the chromatographic columns is six, the volume of the chromatographic columns is 4000 mL/root, and the chromatographic columns are respectively a first chromatographic column 31, a second chromatographic column 32, a third chromatographic column 33, a fourth chromatographic column 34, a fifth chromatographic column 35 and a sixth chromatographic column 36; the number of the chromatographic circulation pumps is six, namely a first circulation pump 41, a second circulation pump 42, a third circulation pump 43, a fourth circulation pump 44, a fifth circulation pump 45 and a sixth circulation pump 46; six chromatographic columns are sequentially connected in series from head to tail through the circulating pipeline to form a loop; six chromatographic circulating pumps are respectively arranged between two connected chromatographic columns.
In order to control the simulated moving bed chromatographic separation system conveniently, each chromatographic column is connected with the raw material pump 1 respectively, and each connecting pipeline is provided with a raw material automatic switch valve 7; each chromatographic column is connected with the water pump 2 respectively, and each connecting pipeline is provided with a water automatic switch valve 8; each chromatographic column is connected with the extraction liquid tank 5 respectively, and each connecting pipeline is provided with an extraction liquid automatic switch valve 9; each chromatographic column is connected with the raffinate tank 6 respectively, and each connecting pipeline is provided with a raffinate automatic switch valve 10. And each circulating pipeline connected with the chromatographic column is provided with a circulating automatic switch valve 18.
In order to obtain the value of the accumulated liquid passing volume of the circulating pipeline of the simulated moving bed chromatographic separation system in real time, a first mass flowmeter 11 is further arranged on the circulating pipeline between the outlet of the chromatographic circulating pump and the top end of the chromatographic column.
In order to obtain the value of the accumulated liquid passing volume of the extracting solution of the simulated moving bed chromatographic separation system in real time, each chromatographic column is connected with a pipeline connected with the extracting solution tank 5 through an extracting solution main pipeline; the main extracting solution pipeline is provided with a second mass flowmeter 12 and an extracting solution automatic control regulating valve 14;
in order to obtain the value of the accumulated liquid passing volume of the raffinate of the simulated moving bed chromatographic separation system in real time, each chromatographic column is connected with a pipeline connected with the raffinate tank through a raffinate main pipeline; the raffinate main pipeline is provided with a third mass flowmeter 13 and a raffinate self-control regulating valve 15.
In order to obtain the column top pressure and the column bottom pressure of the chromatographic column in real time, the top end of the chromatographic column, the outlet of the raw material pump 1, the outlet of the water pump 2 and the pipeline between the outlets of the chromatographic circulating pump form a branch pipeline and are connected through a main pipeline; a column top pressure gauge 16 is provided on the main conduit, the column top pressure gauge 16 being adapted to monitor the column top pressure of the chromatography column. A column bottom pressure gauge 17 is arranged on a circulating pipeline between the bottom end of the chromatographic column and the inlet of the chromatographic circulating pump, and the column bottom pressure gauge 17 is suitable for detecting column bottom pressure of the chromatographic column. It should be noted that, the selection of the column top pressure gauge 16 and the column bottom pressure gauge 17 is not unique, and in this embodiment, the remote transmission digital display pressure gauge is used.
The chromatographic separation in the simulated moving bed chromatographic separation system specifically comprises the following steps:
step 1: the method comprises the steps of (1) carrying out self-circulation of feed liquid in a chromatographic column in a simulated moving bed chromatographic separation system, and separating raw materials injected into the system;
step 2: enabling the eluent to enter a simulated moving bed chromatographic separation system, pushing the band to move in the system, thereby achieving the effect of continuously separating components in the column body and simultaneously flowing out raffinate;
step 3: enabling the eluent and the levodopa stock solution to respectively enter different positions of a simulated moving bed chromatographic separation system at the same time, and enabling the extracting solution and the raffinate to flow out from different outlets;
repeating the steps 1-3, and continuously separating out an extracting solution and a raffinate, wherein the raffinate is the levodopa.
The working process of the simulated moving bed chromatographic separation system is specifically as follows:
(1) After the materials are conveyed to the chromatographic columns by the raw material pump 1, the internal circulation is completed in each chromatographic column through each chromatographic circulation pump.
(2) The water pump 2 is started, the automatic water switching valve 8 is opened, the chromatographic column bottom chromatographic circulating pump and the automatic raffinate switching valve 10 are opened, and the levodopa is conveyed to the raffinate tank 6.
(3) After the output of the levodopa is finished, the water pump 2 and the first circulating pump 41 are started, the water automatic switching valve 8 at the top end of the first chromatographic column 31 is opened, and the aqueous solution of the eluent enters the chromatographic column; simultaneously, a chromatographic circulating pump and an extracting solution automatic switching valve 9 at the bottom end of the first chromatographic column 31 are opened, and the discharging flow of the extracting solution is regulated by an extracting solution automatic regulating valve 14, so that the chromatographic column keeps a preset system pressure, and the product is conveyed to an extracting solution tank 5;
simultaneously, starting a raw material pump 1, a fourth circulating pump 44 and a fifth circulating pump 45, opening a raw material automatic switching valve 7 at the top end of the fourth chromatographic column 34, and opening a circulating automatic switching valve 18 at the bottom end of the fourth chromatographic column 34 to enable materials to enter the chromatographic column; meanwhile, the corresponding raffinate automatic switch valve 10 at the bottom end of the fifth chromatographic column 35 is opened, and the discharging flow of the raffinate is regulated by the raffinate automatic control regulating valve 15, so that the separation and purification of the levodopa are realized.
In the purification of the levodopa, the chromatographic separation temperature is 20-30 ℃, the eluent is preferably deionized water, the volume ratio of the eluent to the levodopa stock solution is (4.5-5.0): 1, the flow rate of the eluent is 8-10L/h, and the feeding flow rate of the levodopa stock solution is 8-10L/h.
In the working process of the simulated moving bed chromatographic separation system, the control method of the simulated moving bed chromatographic separation system also relates to the control on and off of each pump body and valve, and the control method is used for controlling the starting and closing of the raw material pump 1, the water pump 2 and the chromatographic circulation pump, and controlling the starting and closing of the raw material automatic switching valve 7, the water automatic switching valve 8, the extracting solution automatic switching valve 9, the raffinate automatic switching valve 10, the extracting solution automatic control regulating valve 14, the raffinate automatic control regulating valve 15 and the circulation automatic switching valve 18 by acquiring data of the column top pressure gauge 16, the column bottom pressure gauge 17, the first mass flowmeter 11, the second mass flowmeter 12 and the third mass flowmeter 13. The control method can realize control through a DCS control system.
In a specific control method, the following principle is followed:
(1) Starting a chromatographic circulating pump, and opening a corresponding circulating automatic switching valve 18 to enable the chromatographic column to perform self circulation;
(2) Acquiring an accumulated volume value according to a first mass flowmeter 11 on a circulating pipeline, and closing a chromatographic circulating pump and a circulating automatic switching valve 18 after the accumulated volume value reaches a preset value A;
(3) Starting the water pump 2 and the chromatographic circulating pump, and opening the corresponding water automatic switching valve 8 and the corresponding circulating automatic switching valve 18 to enable the aqueous solution of the eluent to enter the chromatographic column; opening the automatic raffinate switching valve 10, and regulating the discharge flow of the raffinate through the automatic raffinate control regulating valve 15 to enable the chromatographic column to maintain the preset system pressure;
(4) Acquiring an accumulated volume value according to a third mass flowmeter 13, and closing the water pump 2 and the chromatographic circulating pump, and closing the water automatic switching valve 8, the raffinate automatic switching valve 10 and the circulating automatic switching valve 18 after the accumulated volume value reaches a preset value B;
(5) Starting a water pump 2 and a chromatographic circulating pump, and opening a corresponding water automatic switching valve 8 to enable an aqueous solution of an eluent to enter the chromatographic column; simultaneously, the corresponding automatic extracting solution switching valve 9 is opened, and the discharging flow of the extracting solution is regulated by the automatic extracting solution regulating valve 14, so that the chromatographic column maintains the preset system pressure;
starting a raw material pump 1 and a chromatographic circulating pump, and opening a corresponding raw material automatic switching valve 7 and a corresponding circulating automatic switching valve 18 to enable materials to enter the chromatographic column; simultaneously, the corresponding raffinate automatic switch valve 10 is opened;
(6) And acquiring accumulated volume values according to the second mass flowmeter 12 and the third mass flowmeter 13, and closing the water pump 2, the raw material pump 1 and the chromatographic circulating pump, and closing the water automatic switching valve 8, the raw material automatic switching valve 7 and the circulating automatic switching valve 18 after the accumulated volume values respectively reach a preset value C and a preset value D.
The steps (1) - (6) can be continuously and circularly carried out, so that continuous feeding in the simulated moving bed chromatographic separation system is realized, and meanwhile, the extracting solution and the raffinate are continuously separated.
It should be noted that, in step (1), in the first circulation process, the water pump is required to be manually turned on, the self-circulation is started after adding water to increase the pressure of the chromatographic column to a certain value, in the subsequent circulation process, the water pump is not required to be turned on, the self-circulation accumulation volume is the volume number of the levodopa stock solution in the chromatographic column separated in the chromatographic column by means of the chromatographic circulation pump under the action of the eluent and passing in the fixed flow fixed time, which is the conventional operation in the prior art and is not repeated herein.
Taking the simulated moving bed chromatographic separation system shown in fig. 1 as an example:
the control method of the simulated moving bed chromatographic separation system specifically comprises the following steps:
(1) Starting all chromatographic circulation pumps, and opening all circulation automatic switch valves 18 to enable the chromatographic column to perform self circulation;
(2) Acquiring an accumulated volume value according to a first mass flowmeter 11 on a circulating pipeline, and closing all chromatographic circulating pumps and all circulating automatic switching valves 18 after the accumulated volume value reaches a preset value A;
(3) Starting the water pump 2, the first circulating pump 41, the second circulating pump 42, the third circulating pump 43, the fourth circulating pump 44 and the fifth circulating pump 45, opening the corresponding water automatic switching valve 8 at the top end of the first chromatographic column 31, and opening the corresponding circulating automatic switching valve 18 at the bottom ends of the first chromatographic column 31, the second chromatographic column 32, the third chromatographic column 33 and the fourth chromatographic column 34 to enable the aqueous solution of the eluent to enter the chromatographic columns; opening a raffinate automatic switching valve 10 corresponding to the bottom end of the fifth chromatographic column 35, and regulating the discharge flow of the raffinate through a raffinate automatic control regulating valve 15 to enable the chromatographic column to maintain a preset system pressure;
(4) Acquiring an accumulated volume value according to the third mass flowmeter 13, and closing the water pump 2, the first circulating pump 41, the second circulating pump 42, the third circulating pump 43, the fourth circulating pump 44 and the fifth circulating pump 45 after the accumulated volume value reaches a preset value B, and closing the corresponding water automatic switch valve 8, the raffinate automatic switch valve 10 and the circulating automatic switch valve 18;
(5) Starting the water pump 2 and the first circulating pump 41, and opening the water automatic switching valve 8 at the top end of the first chromatographic column 31 to enable the water solution of the eluent to enter the chromatographic column; simultaneously, a corresponding chromatographic circulating pump and an automatic extracting solution switching valve 9 at the bottom end of the first chromatographic column 31 are opened, and the discharging flow of the extracting solution is regulated by an extracting solution automatic regulating valve 14, so that the chromatographic column maintains the preset system pressure;
simultaneously, starting a raw material pump 1, a fourth circulating pump 44 and a fifth circulating pump 45, opening a raw material automatic switching valve 7 at the top end of the fourth chromatographic column 34, and opening a circulating automatic switching valve 18 at the bottom end of the fourth chromatographic column 34 to enable materials to enter the chromatographic column; simultaneously, the corresponding raffinate automatic switch valve 10 at the bottom end of the fifth chromatographic column 35 is opened, and the discharging flow of the raffinate is regulated by the raffinate automatic control regulating valve 15;
(6) According to the second mass flowmeter 12 and the third mass flowmeter 13, an accumulated volume value is obtained, and after the accumulated volume value reaches a preset C value and a preset D value, the water pump 2, the raw material pump 1, the first circulating pump 41, the fourth circulating pump 44 and the fifth circulating pump 45 are turned off, and the water automatic switching valve 8, the raw material automatic switching valve 7 and the circulating automatic switching valve 18 are turned off.
The steps (1) - (6) are continuously repeated, and it should be noted that in the process of continuously circulating the steps (1) - (6), the first chromatographic column 31, the second chromatographic column 32, the third chromatographic column 33, the fourth chromatographic column 34, the fifth chromatographic column 35 and the sixth chromatographic column 36 are continuously changed in circulation, and the system is continuously fed, and meanwhile, the extracting solution and the raffinate are continuously separated, so as to realize stable production. Taking the following period as an example, the method specifically comprises the following steps:
(1') turning on all the chromatographic circulation pumps, and turning on all the circulation automatic switch valves 18 to make the chromatographic column perform self-circulation;
(2') acquiring an accumulated volume value according to a first mass flowmeter 11 on a circulating pipeline, and closing all chromatographic circulating pumps and all circulating automatic on-off valves 18 after the accumulated volume value reaches a preset value A;
(3') turning on the water pump 2, the second circulation pump 42, the third circulation pump 43, the fourth circulation pump 44, the fifth circulation pump 45 and the sixth circulation pump 46, turning on the water automatic switching valve 8 corresponding to the top end of the second chromatographic column 32, and turning on the water automatic switching valve 18 corresponding to the bottom ends of the second chromatographic column 32, the third chromatographic column 33, the fourth chromatographic column 34 and the fifth chromatographic column 35 to enable the aqueous solution of the eluent to enter the chromatographic columns; opening a raffinate automatic switching valve 10 corresponding to the bottom end of the sixth chromatographic column 36, and regulating the discharge flow of the raffinate through a raffinate automatic control regulating valve 15 to enable the chromatographic column to maintain a preset system pressure;
(4') acquiring an accumulated volume value according to the third mass flowmeter 13, and after the accumulated volume value reaches a preset value B, closing the water pump 2, the second circulating pump 42, the third circulating pump 43, the fourth circulating pump 44, the fifth circulating pump 45 and the sixth circulating pump 46, and closing the water automatic switching valve 8 and the raffinate automatic switching valve 10;
(5') turning on the water pump 2 and the second circulating pump 42, and opening the water automatic switching valve 8 at the top end of the second chromatographic column 32 to enable the aqueous solution of the eluent to enter the chromatographic column; simultaneously, a corresponding chromatographic circulation pump and an automatic extracting solution switching valve 9 at the bottom end of the second chromatographic column 32 are opened, and the discharging flow of the extracting solution is regulated by an extracting solution automatic regulating valve 14, so that the chromatographic column maintains the preset system pressure;
simultaneously, starting a raw material pump 1, a fifth circulating pump 45 and a sixth circulating pump 46, opening a raw material automatic switching valve 7 corresponding to the top end of the fifth chromatographic column 35, and opening a circulating automatic switching valve 18 corresponding to the bottom end of the fifth chromatographic column 35 to enable materials to enter the chromatographic column; simultaneously, the corresponding raffinate automatic switch valve 10 at the bottom end of the sixth chromatographic column 36 is opened, and the discharging flow of the raffinate is regulated by the raffinate automatic control regulating valve 15;
(6') acquiring cumulative volume values according to the second mass flowmeter 12 and the third mass flowmeter 13, and after the cumulative volume values reach a preset value C and a preset value D respectively, closing the water pump 2, the raw material pump 1, the second circulating pump 42, the fifth circulating pump 45 and the sixth circulating pump 46, and closing the water automatic switching valve 8, the raw material automatic switching valve 7 and the circulating automatic switching valve 18.
The control method can realize control through a DCS control system, and column top pressure, column bottom pressure, feeding and discharging flow and the like of the chromatographic column are regulated through PID of the DCS.
On the basis of the L-dopa purification by using the simulated moving bed chromatographic separation system, one of the characteristics of the embodiment of the invention is that the simulated moving bed chromatographic separation system adopts a chromatographic column filled with nonpolar macroporous adsorption resin, and the nonpolar macroporous adsorption resin is self-made. Specifically, the conventional macroporous adsorption resin uses styrene as a polymerization monomer, divinylbenzene as a crosslinking agent, toluene and xylene as pore-forming agents, and the styrene and the xylene are crosslinked and polymerized with each other to form the nonpolar macroporous adsorption resin. In the embodiment of the present invention, the ratio of divinylbenzene to styrene is generally set to 0.4:1, and in order to improve moldability of the resin, the network pore size in the resin is reduced, and the ratio of divinylbenzene to styrene is increased to (0.45-0.75): 1, preferably 0.6:1. The nonpolar macroporous adsorption resin has the granularity range (0.45-0.65 mm), the average grain diameter of 0.5-0.6mm, uniform granularity, the whole sphere rate of more than or equal to 98 percent, the levodopa and the impurity tyrosine can be thoroughly separated after the resin is used, the system has stable feeding and discharging operations, and the discharging index is also in a controllable range. The adding proportion of toluene and xylene is not particularly required, but the adding proportion of toluene and xylene meets the requirements of the macroporous adsorption resin for medical use: the resin residue toluene was <890ppm and xylene was <2170ppm.
Further, the simulated moving bed chromatographic separation technology has been developed from the 60 th century of the 20 th century to be applied to the fields of petroleum, fine chemical industry, biological fermentation, medicine, food, etc., and when applied to these fields, the first-step cycle cumulative value (i.e., the cumulative passing volume of the chromatographic column during the self-cycle process) is mostly in the range of 0.4 to 0.6BV (BV means bed volume, here means resin volume in the column), and if the raw material is not completely separated within this range, it can be basically characterized as that the fine purification of the raw material cannot be performed by the simulated moving bed chromatographic separation technology, but other purification modes, such as multiple repeated crystallization experiments, are selected.
The second characteristic of the embodiment of the invention is that in the self-circulation process of the chromatographic column, the node for stopping self-circulation is the volume of the feed liquid accumulated in the circulation pipeline of the simulated moving bed chromatographic separation system to reach 0.8-1.0BV. For a specific analysis: l-dopa chemical molecular structure C 9 H 11 NO 4 Contains a benzene ring and a carboxyl group, which are very similar in structure to dopamine, and thus levodopa is also known as a dopamine precursor. And tyrosine chemical molecular structural formula C 9 H 11 NO 3 Levodopa is an intermediate product of tyrosine forming catecholamine, so that it is difficult to thoroughly separate levodopa from tyrosine in industrial production. In the embodiment of the invention, in the application of the simulated moving bed chromatographic separation technology, self-made chromatographic separation technology is selectedAfter the nonpolar macroporous adsorption resin, the convention is broken, the circulation volume is increased, the band of the two mixtures in the chromatographic resin column is increased, and the adsorption effect of the macroporous adsorption resin on the two compounds is strong and weak, so that the maximum separation is achieved.
The invention will be described in detail below by way of examples:
example 1
The method for separating and purifying the levodopa of the embodiment comprises the following steps:
and (3) taking the levodopa stock solution after microbial fermentation and decoloration and filtration, carrying out chromatographic separation in a simulated moving bed chromatographic separation system, wherein the flow rate of an eluent is 8L/h, and the feeding flow rate of the levodopa stock solution is 8L/h to obtain raffinate, namely the separated and purified levodopa.
The chromatographic resin adopted in the chromatographic separation is nonpolar macroporous adsorption resin. The temperature of the chromatographic separation was 25 ℃.
The levodopa stock solution is produced by a microbial fermentation method, decolorized and filtered stock solution, the concentration of the stock solution is 30g/L, and ascorbic acid is added to prevent oxidation, and the pH value of the stock solution is 1-3. The eluent adopted by the chromatographic separation is deionized water. The volume ratio of the eluent to the levodopa stock solution is 5:1.
The simulated moving bed chromatographic separation system comprises 6 chromatographic columns, wherein the 6 chromatographic columns are sequentially connected in series from head to tail; the column had a volume of 4000 mL/root and Man Zhu packed with chromatographic separation resin.
In the control process of the simulated moving bed chromatographic separation system, the settings of the preset value A, the preset value B, the preset value C and the preset value D are as follows:
example 2
The method for separating and purifying the levodopa of the embodiment comprises the following steps:
and (3) taking the levodopa stock solution after microbial fermentation and decoloration and filtration, carrying out chromatographic separation in a simulated moving bed chromatographic separation system, wherein the flow rate of an eluent is 10L/h, and the feeding flow rate of the levodopa stock solution is 10L/h to obtain raffinate, namely the separated and purified levodopa.
The chromatographic resin adopted in the chromatographic separation is nonpolar macroporous adsorption resin. The temperature of the chromatographic separation was 25 ℃.
The levodopa stock solution is produced by a microbial fermentation method, decolorized and filtered stock solution, the concentration of the stock solution is 30g/L, and ascorbic acid is added to prevent oxidation, and the pH value of the stock solution is 1-3. The eluent adopted by the chromatographic separation is deionized water. The volume ratio of the eluent to the levodopa stock solution is 5:1.
The simulated moving bed chromatographic separation system comprises 6 chromatographic columns, wherein the 6 chromatographic columns are sequentially connected in series from head to tail; the column had a volume of 4000 mL/root and Man Zhu packed with chromatographic separation resin.
In this example, the composition of the simulated moving bed chromatography separation system and the setting of the preset value were the same as those in example 1.
Example 3
The method for separating and purifying the levodopa of the embodiment comprises the following steps:
and (3) taking the levodopa stock solution after microbial fermentation and decoloration and filtration, carrying out chromatographic separation in a simulated moving bed chromatographic separation system, wherein the flow rate of an eluent is 8L/h, and the feeding flow rate of the levodopa stock solution is 8L/h to obtain raffinate, namely the separated and purified levodopa.
The chromatographic resin adopted in the chromatographic separation is nonpolar macroporous adsorption resin. The temperature of the chromatographic separation was 25 ℃.
The levodopa stock solution is produced by a microbial fermentation method, decolorized and filtered stock solution, the concentration of the stock solution is 30g/L, and ascorbic acid is added to prevent oxidation, and the pH value of the stock solution is 1-3. The eluent adopted by the chromatographic separation is deionized water. The volume ratio of the eluent to the levodopa stock solution is 4.5:1.
In this example, the composition of the simulated moving bed chromatography separation system and the setting of the preset value were the same as those in example 1.
In summary, the test conditions for examples 1-3 are as follows:
comparative example 1
The test conditions consistent with example 3 were maintained, and the preset value A, the preset value B, the preset value C and the preset value D in the control process of the simulated moving bed chromatographic separation system were changed, specifically as follows:
comparative example 2
The test conditions consistent with the test conditions in the embodiment 3 are kept, and the A-step preset value, the B-step preset value, the C-step preset value and the D-step preset value in the control process of the simulated moving bed chromatographic separation system are changed, specifically as follows:
the extracts obtained in examples 1 to 3 and comparative examples 1 and 2 and the corresponding impurity raffinates were taken and subjected to ultraviolet precise liquid phase component measurement. The results were as follows:
according to the embodiment 1-3, the method for separating and purifying the levodopa has good effect of removing impurities such as tyrosine, catechol, pyruvic acid and the like in the raw solution of the levodopa, the yield of the obtained levodopa in the extracting solution reaches more than 99 percent, the purity of the levodopa reaches more than 99.85 percent, and the quality requirement of European Pharmacopoeia (EP) of United States Pharmacopoeia (USP) is met.
From a comparison of example 3 and comparative examples 1 and 2, it is evident that the a-step cycle volume parameter has a significant effect on the purity of levodopa.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (5)
1. A method for separating and purifying levodopa is characterized in that a levodopa stock solution is taken and is subjected to chromatographic separation in a simulated moving bed chromatographic separation system to obtain raffinate, namely the levodopa;
wherein the simulated moving bed chromatographic separation system adopts a chromatographic column filled with nonpolar macroporous adsorption resin, the nonpolar macroporous adsorption resin is mainly formed by cross-linking polymerization of styrene and divinylbenzene, and the adding ratio of the divinylbenzene to the styrene is (0.45-0.75): 1;
the chromatographic separation in the simulated moving bed chromatographic separation system specifically comprises:
step 1: the method comprises the steps of (1) carrying out self-circulation of feed liquid in a chromatographic column in a simulated moving bed chromatographic separation system, and separating raw materials injected into the system;
step 2: enabling the eluent to enter a simulated moving bed chromatographic separation system, pushing the band to move in the system, thereby achieving the effect of continuously separating components in the column body and simultaneously flowing out raffinate;
step 3: enabling the eluent and the levodopa stock solution to respectively enter different positions of a simulated moving bed chromatographic separation system at the same time, and enabling the extracting solution and the raffinate to flow out from different outlets;
repeating the steps 1-3, and continuously separating out an extracting solution and a raffinate, wherein the raffinate is the levodopa;
in the step 1, the self-circulation of the feed liquid is carried out in the chromatographic column until the volume of the feed liquid which passes through in the circulating pipeline of the simulated moving bed chromatographic separation system in an accumulated way reaches 0.8-1.0BV;
the levodopa stock solution is produced by a microbial fermentation method, decolorized and filtered, the concentration of the stock solution is 30g/L, and ascorbic acid is added to prevent oxidation, and the pH value of the stock solution is 1-3;
the simulated moving bed chromatographic separation system comprises 6 chromatographic columns, and the 6 chromatographic columns are sequentially connected in series from head to tail.
2. The method for separating and purifying levodopa according to claim 1, wherein the temperature of the chromatographic separation is 20 ℃ to 30 ℃.
3. The method for separating and purifying levodopa according to claim 1, wherein said eluent is deionized water.
4. The method for separating and purifying levodopa according to claim 1, wherein the volume ratio of said eluent to said levodopa stock solution is (4.5-5.0): 1.
5. The method for separating and purifying levodopa according to claim 1, wherein the flow rate of the eluent is 8-10L/h, and the feed flow rate of the levodopa stock solution is 8-10L/h.
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Effective date of registration: 20240625 Address after: Room 229, No. 88 Kangyang Avenue, Shangyu Economic and Technological Development Zone, Shangyu District, Shaoxing City, Zhejiang Province, 312000 Patentee after: Zhejiang Zhenyuan Biotechnology Co.,Ltd. Country or region after: China Patentee after: Oushangyuan Intelligent Equipment Co.,Ltd. Address before: 300350 6-3-501, Ligang Park, Shuanggang Town, Jinnan District, Tianjin Patentee before: Oushangyuan Intelligent Equipment Co.,Ltd. Country or region before: China |