CN117255942A - Method for separating a mixture of substances - Google Patents
Method for separating a mixture of substances Download PDFInfo
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- CN117255942A CN117255942A CN202280031177.0A CN202280031177A CN117255942A CN 117255942 A CN117255942 A CN 117255942A CN 202280031177 A CN202280031177 A CN 202280031177A CN 117255942 A CN117255942 A CN 117255942A
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- substance
- mixture
- extract
- raffinate
- chromatography
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- 239000000126 substance Substances 0.000 title claims abstract description 195
- 239000000203 mixture Substances 0.000 title claims abstract description 90
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000000284 extract Substances 0.000 claims abstract description 65
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 47
- 230000014759 maintenance of location Effects 0.000 claims abstract description 32
- 239000003480 eluent Substances 0.000 claims abstract description 27
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical group CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 claims description 36
- 239000000463 material Substances 0.000 claims description 29
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims description 26
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 24
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 24
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 24
- 235000021342 arachidonic acid Nutrition 0.000 claims description 18
- 229940114079 arachidonic acid Drugs 0.000 claims description 18
- 230000000770 proinflammatory effect Effects 0.000 claims description 18
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 17
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 16
- 229960004242 dronabinol Drugs 0.000 claims description 16
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims description 15
- 229950011318 cannabidiol Drugs 0.000 claims description 15
- 238000004590 computer program Methods 0.000 claims description 15
- OPGOLNDOMSBSCW-CLNHMMGSSA-N Fursultiamine hydrochloride Chemical group Cl.C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N OPGOLNDOMSBSCW-CLNHMMGSSA-N 0.000 claims description 14
- 230000001373 regressive effect Effects 0.000 claims description 14
- JIWBIWFOSCKQMA-UHFFFAOYSA-N stearidonic acid Natural products CCC=CCC=CCC=CCC=CCCCCC(O)=O JIWBIWFOSCKQMA-UHFFFAOYSA-N 0.000 claims description 14
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims description 13
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical group OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims description 13
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 claims description 13
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 claims description 13
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 claims description 10
- 235000021294 Docosapentaenoic acid Nutrition 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 9
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 claims description 7
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 claims description 7
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 claims description 7
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 7
- 230000001276 controlling effect Effects 0.000 claims description 6
- CZXWOKHVLNYAHI-LSDHHAIUSA-N 2,4-dihydroxy-3-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-propylbenzoic acid Chemical group OC1=C(C(O)=O)C(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 CZXWOKHVLNYAHI-LSDHHAIUSA-N 0.000 claims description 5
- CZXWOKHVLNYAHI-UHFFFAOYSA-N CBDVA Natural products OC1=C(C(O)=O)C(CCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 CZXWOKHVLNYAHI-UHFFFAOYSA-N 0.000 claims description 5
- 229930184725 Lipoxin Natural products 0.000 claims description 5
- 150000002639 lipoxins Chemical class 0.000 claims description 5
- SWTYBBUBEPPYCX-VIIQGJSXSA-N (4Z,7Z,10Z,13Z,15E,19Z)-17-hydroxydocosahexaenoic acid Chemical compound CC\C=C/CC(O)\C=C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O SWTYBBUBEPPYCX-VIIQGJSXSA-N 0.000 claims description 4
- LRWYBGFSVUBWMO-UAAZXLHOSA-N 18(R)-HEPE Chemical compound CC[C@@H](O)\C=C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O LRWYBGFSVUBWMO-UAAZXLHOSA-N 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 150000004665 fatty acids Chemical class 0.000 claims description 4
- 230000006870 function Effects 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 4
- HLHYXXBCQOUTGK-FHCQLJOMSA-N (7R,14S)-dihydroxy-(4Z,8E,10E,12Z,16Z,19Z)-docosahexaenoic acid Chemical compound CC\C=C/C\C=C/C[C@H](O)\C=C/C=C/C=C/[C@H](O)C\C=C/CCC(O)=O HLHYXXBCQOUTGK-FHCQLJOMSA-N 0.000 claims description 3
- 229930003827 cannabinoid Natural products 0.000 claims description 3
- 239000003557 cannabinoid Substances 0.000 claims description 3
- 229940065144 cannabinoids Drugs 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 102000001324 CD59 Antigens Human genes 0.000 claims description 2
- 108010055167 CD59 Antigens Proteins 0.000 claims description 2
- REOZWEGFPHTFEI-JKSUJKDBSA-N Cannabidivarin Chemical compound OC1=CC(CCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-JKSUJKDBSA-N 0.000 claims description 2
- 241001471082 Colocasia bobone disease-associated cytorhabdovirus Species 0.000 claims description 2
- REOZWEGFPHTFEI-UHFFFAOYSA-N cannabidivarine Natural products OC1=CC(CCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 REOZWEGFPHTFEI-UHFFFAOYSA-N 0.000 claims description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims 2
- ZROLHBHDLIHEMS-HUUCEWRRSA-N (6ar,10ar)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCC)=CC(O)=C3[C@@H]21 ZROLHBHDLIHEMS-HUUCEWRRSA-N 0.000 claims 1
- ZROLHBHDLIHEMS-UHFFFAOYSA-N Delta9 tetrahydrocannabivarin Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCC)=CC(O)=C3C21 ZROLHBHDLIHEMS-UHFFFAOYSA-N 0.000 claims 1
- SEEZIOZEUUMJME-FOWTUZBSSA-N cannabigerolic acid Chemical compound CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-FOWTUZBSSA-N 0.000 claims 1
- SEEZIOZEUUMJME-UHFFFAOYSA-N cannabinerolic acid Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1C(O)=O SEEZIOZEUUMJME-UHFFFAOYSA-N 0.000 claims 1
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 20
- 229940090949 docosahexaenoic acid Drugs 0.000 description 10
- 230000033228 biological regulation Effects 0.000 description 6
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 5
- 229940012843 omega-3 fatty acid Drugs 0.000 description 5
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- 239000006014 omega-3 oil Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- UCONUSSAWGCZMV-HZPDHXFCSA-N Delta(9)-tetrahydrocannabinolic acid Chemical compound C([C@H]1C(C)(C)O2)CC(C)=C[C@H]1C1=C2C=C(CCCCC)C(C(O)=O)=C1O UCONUSSAWGCZMV-HZPDHXFCSA-N 0.000 description 2
- QXACEHWTBCFNSA-SFQUDFHCSA-N cannabigerol Chemical compound CCCCCC1=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-SFQUDFHCSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- CRDZYJSQHCXHEG-SFVBTVKNSA-N protectin D1 Chemical compound CC\C=C/C[C@H](O)\C=C/C=C/C=C/[C@H](O)C\C=C/C\C=C/CCC(O)=O CRDZYJSQHCXHEG-SFVBTVKNSA-N 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- HLHYXXBCQOUTGK-NVFVPEJPSA-N (7S,14S)-dihydroxy-(4Z,8E,10E,12Z,16Z,19Z)-docosahexaenoic acid Chemical compound CC\C=C/C\C=C/C[C@H](O)\C=C/C=C/C=C/[C@@H](O)C\C=C/CCC(O)=O HLHYXXBCQOUTGK-NVFVPEJPSA-N 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- CRDZYJSQHCXHEG-HBMALMRFSA-N aspirin-triggered protectin D1 Chemical compound CC\C=C/C[C@@H](O)\C=C/C=C/C=C/[C@H](O)C\C=C/C\C=C/CCC(O)=O CRDZYJSQHCXHEG-HBMALMRFSA-N 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- QXACEHWTBCFNSA-UHFFFAOYSA-N cannabigerol Natural products CCCCCC1=CC(O)=C(CC=C(C)CCC=C(C)C)C(O)=C1 QXACEHWTBCFNSA-UHFFFAOYSA-N 0.000 description 1
- 229940013317 fish oils Drugs 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- AOPOCGPBAIARAV-OTBJXLELSA-N resolvin E1 Chemical compound CC[C@@H](O)\C=C\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O AOPOCGPBAIARAV-OTBJXLELSA-N 0.000 description 1
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- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention relates to a method for separating a first substance from a substance mixture by chromatography, wherein the substance mixture has at least one second substance which is subjected to a higher retention in chromatography than the first substance and a third substance which is subjected to a lower retention in chromatography than the first substance, the substance mixture being fed to a device (1) for chromatography, comprising a plurality of interconnected chromatography columns (2, 3, 4, 5), the substance mixture and an eluent being fed to the device (1), and the second substance being extracted as an extract and the first substance being extracted as a raffinate. The object is achieved according to the invention in that the third substance is extracted as an extract. The third and second substances are suitably extracted together as an extract. The invention further relates to a device (1) for carrying out the method.
Description
Technical Field
The invention relates to a method for separating a first substance from a substance mixture by chromatography, said substance mixture having at least one second substance with a higher retention in the chromatography than the first substance and a third substance with a lower retention in the chromatography than the first substance, said substance mixture being supplied to a device for carrying out chromatography, said device comprising a plurality of interconnected chromatography columns, said substance mixture and an eluent being supplied to said device, and the second substance being extracted as an extract and the first substance being extracted as a raffinate.
Background
Chromatography of the type described above is known through the use of. The substance mixture to be separated is led through a chromatographic column having a stationary phase comprising, for example, a so-called packing consisting of a porous material. Different substances of the mixture of substances are subjected to different retention effects when flowing through the stationary phase, i.e. the substances flow through the stationary phase at different velocities due to different intensity interactions in the stationary phase. This allows separation. The chromatography may be performed in a so-called batch process in which separation is always completed in one single step, but in order to continuously perform the chromatography, a method of interconnecting a plurality of chromatographic columns has been developed. Such chromatography performed on an industrial scale is true moving bed chromatography (TMB) and simulated moving bed chromatography (SMB).
In SMB chromatography, a plurality of chromatographic columns are connected to each other in series. The mixture of substances and the eluent are fed at different junction points between the chromatographic columns. The raffinate and extract are also extracted at other junction sites as raffinate extracts substances that are less retained in chromatography and extract extracts substances that are more retained in chromatography. Thus, the substance mixture can be separated into two different partial substance mixtures by means of known chromatography processes according to the operation of chromatography, wherein the first partial substance mixture contains the substance which is less subject to retention and the second partial substance mixture contains the substance which is more subject to retention.
Disclosure of Invention
The object of the present invention is to enable a more flexible separation of substances by chromatography.
According to the invention, the object is achieved in that the third substance is extracted as an extract.
By means of the invention, substances can be separated from a substance mixture even when other substances are present in the substance mixture which are correspondingly subjected to a retention rate in chromatography which is greater or less than the substance to be separated. It has been necessary to carry out chromatography several times in succession in order to obtain similar results, whereas the substances to be separated can be separated off by carrying out a single chromatography by means of the method according to the invention. The costs for carrying out the separation process are greatly reduced.
In one embodiment of the invention, the chromatographic column forms a plurality of zones, wherein
a) A first zone is formed between the means for introducing an eluent and the means for withdrawing an extract,
b) A second zone is formed between the means for withdrawing the extract and the means for introducing the substance mixture,
c) Forming a third zone between the means for introducing the mixture of substances and the means for withdrawing the raffinate, and
d) A fourth zone is formed between the means for withdrawing raffinate and the means for introducing eluent.
The material flow, in particular the introduction and/or removal flow, is expediently adjusted by the introduction and/or removal device such that a large flow exists in the region between the device for removing raffinate and the device for introducing eluent, so that a third material can be extracted as extract. In such an arrangement of the chromatographic apparatus, the third substance is pressed into zone I, from which the extract is extracted, unlike what is usual in known chromatographic methods. When using known chromatographic processes, the third substance is extracted as raffinate due to its lower retention compared to the first substance, whereas according to the invention the third substance is extracted as extract.
It has proven to be particularly advantageous to extract the third and the second substance together as an extract.
In one embodiment of the invention, the device for introducing the eluent, the device for removing the extract, the device for introducing the substance mixture and the device for introducing the raffinate have a plurality of inlet or outlet connections which are arranged between different chromatographic columns. The feed or discharge connection is preferably provided with a valve, by means of which the respective material flow, in particular the feed and/or discharge flow, of the material mixture, the eluent, the extract and/or the raffinate through the respective feed or discharge connection can be adjusted. According to the invention, the respective material flows are such that the zones are formed in different chromatographic columns in the device in a changing manner. In this way, the chromatography according to the invention can be carried out as TMB or SMB process.
In a preferred embodiment of the invention, the first substance content in the raffinate is greater than the first substance content in the substance mixture, and preferably the second and/or third substance content in the extract is greater than the second and/or third substance content in the substance mixture. The content of the first material in the raffinate is maximized and in particular the content of the second and/or third material in the extract is maximized.
The content of the first substance in the extract is suitably less than the content of the first substance in the mixture of substances, and the content of the second and/or third substance in the raffinate is preferably less than the content of the second or third substance in the mixture of substances.
The content of the first substance in the extract is preferably smaller than the content of the first substance in the raffinate, and the content of the second and/or third substance in the raffinate is preferably larger than the content of the second or third substance in the extract.
In a particularly preferred embodiment of the invention, the respective material flows are adjusted such that at least one of the above-described content relationships is achieved in the raffinate or extract. Preferably, the adjustment is carried out continuously, particularly preferably as a regulation and/or control.
The chromatographic apparatus expediently comprises at least one device for determining the material properties of the raffinate and/or extract, if appropriate also for determining the material properties of the material mixture and/or eluate, in particular here the content of the content material of the raffinate, extract, material mixture and/or eluate.
The flow of the substance mixture, the eluent, the raffinate and/or the extract in the apparatus is adjusted, particularly preferably regulated, as a function of the result of the determination of the substance properties by means of the sensor.
In one embodiment of the invention, the control and/or regulation is carried out in such a way that the content of the first substance in the raffinate is maximized and preferably the content of the second and/or third substance in the raffinate is minimized.
In one embodiment of the invention, the substance mixture is or comprises a fatty acid mixture, preferably a mixture of unsaturated fatty acids, in particular polyunsaturated fatty acids. The fatty acid mixture particularly preferably comprises omega-3 fatty acids.
The first substance to be separated from the fatty acid mixture is suitably a polyunsaturated fatty acid, preferably an omega-3 fatty acid, particularly preferably eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA). If EPA is separated from the substance mixture as a first substance, DHA and/or arachidonic acid (ARA) which are subjected to a large retention in chromatography may form a second substance. Stearidonic acid (SDA) may be the third substance that has greater retention than EPA in chromatography and is extracted as an extract. The purpose of extracting omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), may be to produce a product containing the corresponding omega-3 fatty acids in particularly high concentrations.
Furthermore, the method may be carried out with the aim of reducing the content of a defined substance in the substance mixture. Arachidonic acid can be extracted from omega-3 fatty acids, for example, by the process as a first substance and thus as a raffinate, in order to reduce the content of arachidonic acid. And then extracting the target product as an extract.
In a further embodiment of the invention, the substance mixture is or comprises a carboxylic acid mixture, preferably a mixture comprising cannabinoids. The first substance is a suitable Cannabidiol (CBD). Alternatively, tetrahydrocannabinol (THC), in particular Δ9-THC and/or Δ8-THC, may constitute the first substance. This proves to be advantageous when THC should be removed from the carboxylic acid mixture, in particular from cannabinoids.
If CBD is isolated from carboxylic acid as the first material, then sub-Cannabidiol (CBDV), tetrahydrocannabinol (THCV) and/or sub-Cannabidiol (CBDVA) may be formed in the second material. The third substance may be formed from Cannabigerol (CBG), tetrahydrocannabinolic acid (THCBA), Δ9-and/or Δ8-THC and/or cannabigerol acid (CBGA).
In another embodiment of the invention, the mixture of substances is or comprises a mixture of pro-inflammatory regressions mediators (PRMs), preferably 18-HEPE, 17-HDHA and/or 14-HDHA, and/or comprises a mixture of specific pro-inflammatory regressions mediators (SPMs), preferably lipoxin, resolvins, protectins and/or Maresins.
In a further embodiment of the invention, the first substance is a metabolite of polyunsaturated fatty acids, preferably a metabolite of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) and/or docosapentaenoic acid (DPA), or has the same chemical composition as the metabolite.
In one embodiment of the invention, the method is suitably carried out such that at least one pro-inflammatory regressive medium (PRM) and/or specific pro-inflammatory regressive medium (SPM) is isolated from the substance mixture, preferably derived from EPA, DHA or/and from DPA.
The pro-inflammatory regressive medium (PRM) is preferably at least one of the group of: 18-HEPE, 17-HDHA, 14-HDHA.
The specific pro-inflammatory regressive medium (SPM) is preferably at least one of the group of: lipoxin, resolvins, protectins, maresins.
The lipoxin is preferably at least one of the group of: lxA4 (5S, 6R, 15S-trihydroxy-7E, 9E, 11Z, 13E-ETE), lxB4 (5S, 14R, 15S-trihydroxy-6E, 8Z, 10E, 12E-ETE), 15-epi-LxA4 (5S, 6R, 15R-trihydroxy-7E, 9E, 11Z, 13E-eicosatetraenoic acid), 15-epi-LxB4 (5S, 14R, 15R-trihydroxy-6E, 8Z, 10E, 12E-eicosatrienoic acid).
The resolvins are suitably derived from EPA, DHA or/and DPA.
The resolvins are preferably
-at least one of the group of: rvE1 (5S, 12R, 18R-trihydroxy-6Z, 8E, 10E, 14Z, 16E-EPA), 18S-RvE (5S, 12R, 18S-trihydroxy-6Z, 8E, 10E, 14Z, 16E-EPA), rvE2 (5S, 18R-dihydroxy-6E, 8Z, 11Z, 14Z, 16E-EPA), rvE3 (17R, 18R/S-dihydroxy-5Z, 8Z, 11Z, 13E, 15E-EPA),
and/or
-at least one of the group of: rvDl (7S, 8R, 17S-trihydroxy-4Z, 9E, 11E, 13Z, 15E, 19Z-DHA), rvD2 (7S, 16R, 17S-trihydroxy-4Z, 8E, 10Z, 12E, 14E, 19Z-DHA), rvD3 (4S, 11R, 17S-trihydroxy-5Z, 7E, 9E, 13Z, 15E, 19Z-DHA), rvD4 (4S, 5R, 17S-trihydroxy-6E, 8E, 10Z, 13Z, 15E, 19Z-DHA), rvD5 (7S, 17S-dihydroxy-4Z, 8E, 10Z, 13Z, 15E, 19Z-DHA), rvD6 (4S, 17S-dihydroxy-5E, 7Z, 10Z, 13Z, 15E, 19Z-DHA),
and/or
-at least one of the group of: rvTl (7, 13R, 20-trihydroxy-8E, 10Z, 14E, 16Z, 18E-DPA), rvT2 (7, 8, 13R-trihydroxy-9E, 11E, 14E, 16Z, 19Z-DPA), rvT3 (7, 12, 13R-trihydroxy-8Z, 10E, 14E, 16Z, 19Z-DPA), rvT4 (7, 13R-dihydroxy-8E, 10Z, 14E, 16Z, 19Z-DPA).
The protectin is suitably derived from DHA or/and DPA.
The protecting element is preferably
-at least one of the group of: PD1 or NPD1 (10R, 17S-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA), PDX (10S, 17S-dihydroxy-4Z, 7Z, 11E, 13Z, 15E, 19Z-DH A), 22-hydroxy-PD 1 (10R, 17S, 22-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA), 17-epi-PD1 or AT-PD1 (10R, 17R-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA), 10-epi-PD1 or ent-AT-NPD1 (10S, 17S-dihydroxy-4Z, 7Z, 11E, 13E, 15Z, 19Z-DHA),
and/or
-at least one of the group of: PD1n-3 (10, 17-dihydroxy-7, 11, 13, 15, 19-DPA), PD2n-3 (16, 17-dihydroxy-7, 10, 12, 14, 19-DPA).
The Maresin is suitably derived from DHA or/and DPA.
The Maresin is preferably
-at least one of the group of: maR1 (7R, 14S-dihydroxy-4Z, 8E, 10E, 12Z, 16Z, 19Z-DHA), maR2 (13R, 14S-dihydroxy-4Z, 7Z, 9E, 11E, 16Z, 19Z-DHA), 7-epi-MaR1 (7S, 14S-dihydroxy-4Z, 8E, 10Z, 12E, 16Z, 19Z-DHA), maR-L1 (14S, 22-dihydroxy-4Z, 7Z, 10Z, 12E, 16Z, 19Z-DHA), maR-L2 (14R, 22-dihydroxy-4Z, 7Z, 10Z, 12E, 16Z, 19Z-DHA),
and/or
-at least one of the group of: maR1n-3 (7S, 14S-dihydroxy-8E, 10E, 12Z, 16Z, 19Z-DPA), maR2n-3 (13, 14-dihydroxy-7, 9, 111, 16, 19-DPA), maR3n-3 (13, 14-dihydroxy-7, 9, 111, 16, 19-DPA).
The invention also relates to a device with which the described separation method can be carried out. In addition to the chromatographic column, the introduction and/or removal means, the apparatus preferably comprises means for determining the material properties of the raffinate and/or extract, in particular for determining the content of the content material. By means of the detection device, physical properties, in particular light absorption, fluorescence, light scattering and/or thermal conductivity, and/or chemical properties, such as coloration or the like, are preferably obtained, and the substance content is determined therefrom.
The apparatus preferably further comprises means for adjusting the substance mixture, the eluent, the flow of the raffinate and/or the extract, in particular the inlet and/or outlet flow.
In a particularly preferred embodiment of the invention, the device has means for regulating and/or controlling the material flow, in particular the inlet and/or outlet flow, through the inlet and/or outlet means as a function of the result of the determination by the detection means. Preferably, the regulating and/or controlling device is configured to adjust the respective material flow such that at least one of the above-described content relationships is achieved in the raffinate or extract.
The invention further relates to a computer program product by means of which the method according to the invention can be implemented. The computer program product may suitably be loaded directly into the internal memory of a digital computer and comprises software parts with which the steps of the method according to the invention can be performed when the computer program is run on the computer. The computer program product preferably has an interface for cooperation with the device according to the invention. The computer program product may form the control and/or regulation device or be part of the control and/or regulation device. The computer program product is preferably configured, in particular because of the interface, for processing the result of the determination made by the detection device and for adjusting the lead-in and/or lead-out device.
The computer program product is suitably configured to perform a single, a plurality or all of the method steps when the computer program product is run on a computer.
The computer program is preferably a computer program product stored on a volatile or non-volatile data carrier, preferably RAM, ROM, DRAM, SRAM, EPROM, EEPROM or similar, or on a device, in particular a personal computer, a device with an embedded processor, or a signal sequence representing data suitable for transmission over a computer network, in particular the internet.
The invention further relates to a data carrier signal for transmitting said computer product.
Drawings
The present invention will be described in detail below with reference to examples and drawings related to the examples.
Wherein:
figure 1 schematically shows a device according to the invention,
FIG. 2 shows the device according to FIG. 1 in a different position, and
FIG. 3 shows a schematic graph of retention time, an
Fig. 4 and 5 show schematic graphs of the retention times of different substances of a substance mixture.
Detailed Description
Fig. 1 schematically shows a chromatography apparatus 1 according to the invention comprising chromatography columns 2, 3, 4, 5 connected to each other such that the columns are in flow connection with each other. Interfaces 10, 11, 12 and 13 are arranged between the chromatographic columns. Each of said interfaces 10, 11, 12, 13 is connected to means 6 for introducing an eluent, means 7 for withdrawing an extract, means 8 for introducing a mixture of substances and means 9 for withdrawing a raffinate. Each of the devices 6, 7, 8, 9 has a valve, by means of which the eluent, extract, substance mixture or raffinate stream, in particular the inlet and/or outlet stream, in particular the size of the respective stream, can be adjusted.
The apparatus comprises a sensor 14 for determining the content of the first substance in the extract and a sensor 15 for determining the content of the first substance in the raffinate.
The device 1 furthermore has means 16 for regulating and/or controlling the inlet and/or outlet flow, in particular by adjusting the valve. The regulating and/or controlling device 16 preferably comprises an embedded processor, on which a computer program is stored, which computer program is arranged to carry out the regulation and/or control in the case of processing the data provided by the sensors 14, 15.
Depending on the open or closed position of the different valves, the location of the supply of the eluent or substance mixture and the location of the removal of the extract or raffinate may be set. Thus, the zones I, II, III, IV can be formed alternately in different chromatographic columns 2, 3, 4, 5, wherein
a) The first zone I is formed between the interface for introducing the eluent and the interface for withdrawing the extract,
b) The second zone II is formed between the interface for the extraction and the interface for the introduction of the substance mixture,
c) A third zone III is formed between the interface for introducing the mixture of substances and the interface for withdrawing the raffinate, and
d) The fourth zone IV is formed between the interface to export the raffinate and the interface to import the eluent feed.
The control and/or regulation device 16 may be provided for adjusting the position of the valve in dependence on the signal of the sensor 16 in order to adjust the material flow, in particular the inlet and/or outlet flow. By adjusting the different valves, the zones I, II, III, IV can be distributed differently in the columns 2, 3, 4, 5. The valve position is set such that the first substance can be extracted as raffinate. Fig. 2a shows the device 1 according to the invention in a valve switching position in which the chromatographic column 2 constitutes zone I, the chromatographic column 3 constitutes zone II, the chromatographic column 4 constitutes zone III and the chromatographic column 5 constitutes zone IV.
By switching the valves, a zone I, II, III, IV can be formed in the respective different columns 2, 3, 4, 5, e.g. in the respective valve switching state, as shown in fig. 2b, column 2 can form zone IV, column 3 can form zone I, column 4 can form zone II, column 5 can form zone III. The switching of the valves is basically carried out as known from the known TMB or SMB chromatography, but taking into account the preconditions described below.
The implementation of the method according to the invention is described in detail with reference to fig. 3, which shows the retention times of the different substances A, B, C, D and E of the substance mixture. Substance D should be separated from the substance mixture. As shown in fig. 3, substance D has a longer retention time than substance A, B, C and shorter retention time than substance E. In order to be able to act as raffinate D, the inlet and outlet streams are arranged such that they are able to act as raffinate D after flowing through zone III. Substance A, B, C, which has a shorter retention time than substance D, is extracted as an extract after zone I. According to the invention, it is furthermore possible in particular to arrange the inlet and outlet streams such that a stream is formed in zone IV in which substance E can be pressed into zone I and can be extracted as an extract together with substance A, B, C.
In a specific first embodiment, the isolation process according to the invention is carried out on a polyunsaturated fatty acid mixture. The substance mixtures, in particular oils, such as fish oils, algae oils or/and linseed oils, comprise DHA, ARA, EPA and SDA. The corresponding retention times are shown in fig. 4. EPA should be extracted as raffinate.
DHA and ARA have a retention time less than EPA. In contrast, SDA has a longer retention time. According to conventional chromatographic methods, it is necessary to first separate substances from DHA and ARA on the one hand and EPA and SDA on the other hand, and subsequently to carry out a further separation of the separated parts with EPA and SDA in order to separate these two components, whereas, as described above, when carrying out the method according to the invention, DHA and ARA are extracted not only as extracts, but also SDA is extracted as extracts when the feed and discharge streams are set up accordingly. EPA extraction was performed only as raffinate.
TABLE 1
Table 1 shows that when different streams Q are set in zone IV IV When different amounts of SDA and EPA can be achieved in the raffinate. When a larger stream is provided in zone IV, the lowest SDA content can be achieved. As can also be seen from table 1, the different flows can be set in the region I, II, III, IV in such a way that different material flows, in particular eluents (Q Eluent ) Mixture of substances (Q) SG ) Raffinate (Q) Rat ) And extract (Q) Extr ) Is provided for the ingress and/or egress streams.
In another embodiment it is provided that ARA is extracted as an extract from the same substance mixture in order to remove arachidonic acid from the substance mixture, the retention time of which is shown in fig. 4. In this case, the material flow is adjusted such that EPA and SDA are pressed into zone I, whereby they can be extracted as an extract together with DHA. It will be appreciated that for this purpose a greater flow rate must be provided in zone IV than in the conventional use of SMB chromatography.
In another embodiment, the separation process is performed on a mixture of materials containing cannabidiol. FIG. 5 schematically graphically illustrates retention times of selected individual substances of a mixture of substances, namely CBDVA, CBD, Δ9-THC, Δ8-THC and CBGA.
The aim is to obtain CBD from the physical mixture, for which purpose the material flow is set up in such a way that CBD can be extracted as the sole raffinate when chromatography is carried out. CBDVA with a retention time lower than CBD, Δ9-THC with a retention time higher than CBD, Δ8-THC and CBGA are extracted together as an extract.
Furthermore, THC can also be eliminated from the cannabidiol mixture mentioned above by the process of the present invention by adjusting the material flow such that Δ9-THC and Δ8-THC are extracted together as a raffinate. CBDVA and CBD with retention times lower than Δ9-THC and Δ8-THC and CBGA with retention times higher than Δ9-THC and Δ8-THC are extracted together as an extract.
Claims (19)
1. Method for separating a first substance from a substance mixture by chromatography, the substance mixture having at least one second substance which is subjected to a higher retention in chromatography than the first substance and at least one third substance which is subjected to a lower retention in chromatography than the first substance, the substance mixture being supplied to a device (1) for chromatography, the device comprising a plurality of interconnected chromatography columns (2, 3, 4, 5), the substance mixture and an eluent being supplied to the device (1), and the second substance being extracted as an extract and the first substance being extracted as a raffinate,
it is characterized in that the method comprises the steps of,
and extracting a third substance as an extract.
2. The method of claim 1, wherein the third and second substances are extracted together as an extract.
3. The method according to claim 1 or 2, wherein the chromatographic column (2, 3, 4, 5) forms a zone (I, II, III, IV), wherein
a) A first zone (I) is formed between the means (6) for introducing the eluent and the means (7) for removing the extract,
b) A second zone (II) is formed between the means (7) for removing the extract and the means (8) for introducing the substance mixture,
(c) A third zone (III) is formed between the means (8) for introducing the mixture of substances and the means (9) for withdrawing the raffinate, and
d) A fourth zone (IV) is formed between the means (9) for withdrawing raffinate and the means (6) for introducing eluent.
4. A method according to claim 3, characterized in that the material flow, in particular the inlet flow and/or the outlet flow, is adjusted by means of the aforementioned inlet and/or outlet means (6, 7, 8, 9) such that a large flow is present in the zone (IV) between the means (9) for outlet raffinate and the means (6) for inlet eluent, such that a third material can be extracted as extract.
5. A process according to any one of claims 1 to 4, characterized in that the first substance content in the raffinate is greater than the first substance content in the substance mixture, and preferably the second substance content in the extract is greater than the second substance content in the substance mixture and/or the third substance content in the extract is greater than the third substance content in the substance mixture.
6. The method according to any one of claims 1 to 5, characterized in that the means (6) for introducing the eluent, the means (7) for discharging the extract, the means (8) for introducing the substance mixture and the means (9) for discharging the raffinate have a plurality of inlet or outlet interfaces (10, 11, 12, 13) between different chromatographic columns (2, 3, 4, 5), and that the respective substance flows through the inlet or outlet interfaces (10, 11, 12, 13) are adapted such that the zones (I, II, III, IV) are formed in the different chromatographic columns (2, 3, 4, 5) in a changing manner in the apparatus (1).
7. The method according to any one of claims 1 to 6, characterized in that a substance property, in particular a content of a content substance, of the raffinate and/or the extract is determined with at least one sensor (14), and that the flow of the substance mixture, the eluent, the raffinate and/or the extract is adjusted, in particular regulated, in the apparatus (1) as a function of the result of the determination of the substance property.
8. The method according to any one of claims 1 to 7, characterized in that the substance mixture is or comprises a fatty acid mixture, preferably or comprises a mixture of unsaturated fatty acids, in particular polyunsaturated fatty acids, and/or comprises a carboxylic acid mixture, preferably or comprises a mixture of cannabinoids, and/or comprises a mixture of pro-inflammatory regressions mediators (PRMs), preferably 18-HEPE, 17-HDHA and/or 14-HDHA, and/or comprises a mixture of specific pro-inflammatory regressions mediators (SPM), preferably lipoxin, resolvins, protectins and/or maresins.
9. The method according to any one of claims 1 to 8, wherein the first substance is a polyunsaturated fatty acid, preferably eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), or is Cannabidiol (CBD) or Tetrahydrocannabinol (THC).
10. The method according to any one of claims 1 to 9, wherein,
a) The third substance is stearidonic acid (SDA) and/or the second substance is arachidonic acid (ARA) and/or docosahexaenoic acid (DHA),
b) The third substance is stearidonic acid (SDA) and/or eicosapentaenoic acid (EPA) and/or the second substance is arachidonic acid (ARA),
or alternatively
c) The third substance is Tetrahydrocannabinol (THC), CBGA and/or CBG and/or the second substance is CBDVA, THCV and/or CBDV.
11. The method according to any one of claims 1 to 8, characterized in that the first substance is a metabolite of polyunsaturated fatty acids, preferably a metabolite of eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) and/or docosapentaenoic acid (DPA), or has the same composition as the metabolite.
12. The method according to any one of claims 1 to 11, characterized in that at least one pro-inflammatory regressive medium (PRM), preferably 18-HEPE, 17-HDHA and/or 14-HDHA, is extracted from the substance mixture, and/or at least one specific pro-inflammatory regressive medium (SPM), preferably lipoxin, resolvin, protectin and/or Maresin is extracted.
13. The method of any one of claims 1 to 12, wherein the first substance is a pro-inflammatory regressive medium (PRM) and/or a specific pro-inflammatory regressive medium (SPM).
14. The method according to any one of claims 1 to 13, wherein,
a) The third substance is pro-inflammatory regressive medium (PRM) and/or specific pro-inflammatory regressive medium (SPM) and/or the second substance is arachidonic acid (ARA) and/or docosahexaenoic acid (DHA),
b) The third substance is a pro-inflammatory regressive medium (PRM) and/or a specific pro-inflammatory regressive medium (SPM), and/or the second substance is eicosapentaenoic acid (EPA) and/or arachidonic acid (ARA),
or alternatively
c) The third substance is a pro-inflammatory regressive medium (PRM) and/or a specific pro-inflammatory regressive medium (SPM), and/or the second substance is docosapentaenoic acid (DPA).
15. Apparatus for separating a first substance from a substance mixture by chromatography, the apparatus comprising a plurality of interconnected chromatography columns (2, 3, 4, 5) and having means for introducing an eluent, means for withdrawing an extract and means for withdrawing a raffinate, the substance mixture having at least one second substance which is subject to a retention effect higher than the first substance in chromatography and at least one third substance which is subject to a retention effect lower than the first substance in chromatography, the apparatus being arranged for extracting the second substance as an extract and the first substance as a raffinate,
it is characterized in that the method comprises the steps of,
the apparatus is arranged for extracting a third substance as an extract.
16. The apparatus according to claim 15, characterized in that the apparatus has means for adjusting the incoming flow and/or the outgoing flow of the substance mixture, the eluent, the raffinate and/or the extract such that the third substance and the second substance are extracted together as an extract.
17. The device according to claim 15 or 16, characterized in that the device has means (16) for adjusting and/or controlling the material flow, in particular the inlet flow and/or the outlet flow, through the inlet and/or outlet means (6, 7, 8, 9) as a function of the result of the determination with at least one sensor (14, 15) for determining the material properties, in particular the content material content, of the raffinate and/or the extract.
18. A computer program product directly loadable into the internal memory of a digital computer and comprising the following software parts: when the computer program product is run on a computer, steps of a method for controlling and/or regulating a substance separation device are carried out with the software component, wherein the substance separation device comprises a plurality of interconnected chromatography columns (2, 3, 4, 5) and is designed for separating a first substance from a substance mixture, which substance mixture has at least one second substance which, when the chromatography is carried out, is subjected to a higher retention than the first substance and a third substance which, when the chromatography is carried out, is subjected to a lower retention than the first substance, the substance mixture and an eluent are supplied to the device (1), and the second substance is extracted as an extract and the first substance is extracted as a raffinate,
it is characterized in that the method comprises the steps of,
in the device (1), the material mixture, the eluent, the material flow of the raffinate and/or the extract, in particular the inlet and/or outlet flow, is adjusted such that a third material is extracted as an extract.
19. A data carrier signal conveying the computer program product of claim 18.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LULU500093 | 2021-04-27 | ||
| LULU500567 | 2021-08-24 | ||
| LU500567 | 2021-08-24 | ||
| PCT/EP2022/061251 WO2022229284A1 (en) | 2021-04-27 | 2022-04-27 | Method for separating a mixture |
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|---|---|
| CN117255942A true CN117255942A (en) | 2023-12-19 |
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| CN202280031177.0A Pending CN117255942A (en) | 2021-04-27 | 2022-04-27 | Method for separating a mixture of substances |
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