CHROMATOGRAPHY METHOD AND DEVICE, IN PARTICULAR METHOD AND DEVICE FOR SUPERCRITICAL LIQUID CHROMATOGRAPHY

Abstract

This version will replace all prior versions in the application: A chromatography method in which a starting material is separated into fractions and at least one of the fractions which have at least a predetermined target content of at least one target component of the starting material is derived as a target product fraction. The fractions which do not have the predetermined target content form residual fractions and at least part of at least one of the residual fractions is added to the starting material still to be separated. At least part of at least one of the residual fractions of which the content of the target component differs less from the predetermined target content than the target component content of the starting material is added to the starting material still to be separated. The residual fractions of which the target component content differs more from the predetermined target content than that of the starting material are diverted for further handling.

Claims

1-17. (canceled)

18. A chromatography method, comprising the steps of: separating a starting material to be separated into fractions by chromatography; diverting off at least one of the fractions having at least a defined target content of at least one target component from the starting material as a target product fraction, wherein the fractions that do not have the defined target content form residual fractions; and adding at least a portion of at least one of the residual fractions to the starting material yet to be separated.

19. The method according to claim 18, including adding at least a portion of at least one of the residual fractions, whose content of the target component varies to a lesser degree from the defined target content than the target component content of the starting material, to the starting material yet to be separated.

20. The method according to claim 18, including diverging off the residual fractions whose target component content varies to a greater degree from the defined target content than that in the starting material for further handling.

21. The method according to claim 20, wherein the defined target content is a minimum content and/or a maximum content.

22. The method according to claim 20, including determining a content of the target component in the starting material and in the fractions, and comparing the target component contents of the residual fractions with those of the starting material.

23. The method according to claim 22, including determining a content of at least two different target components in the starting material and in the fractions and comparing the different target component contents of the residual fractions with those of the starting material.

24. The method according to claim 18, including carrying out the method steps continuously.

25. The method according to claim 22, including automatically carrying out at least the determining and the comparing of the target component contents and a feeding of the residual fraction to the starting material to be separated.

26. The method according to claim 18, including feeding the residual fraction to the starting material to be separated before separation thereof by chromatography, the starting material and the residual fraction being mixed before the separation.

27. The method according to claim 26, including controlling a flow rate of the residual fraction which is fed to the starting material to be separated before separation thereof as a function of the content of the target component in the starting material and/or in the target product fraction.

28. The method according to claim 18, wherein the starting material comprises a mixture of fatty acids and/or derivatives thereof, and/or a mixture of carboxylic acids and/or derivatives thereof, and/or a mixture containing a metabolite of a polyunsaturated fatty acid, or a substance having the same composition as the metabolite, and/or a mixture containing at least one pre-resolving mediator and/or a specialized pre-resolving mediator, and/or a mixture containing at least one pre-resolving mediator and/or specialized pre-resolving mediator.

29. The method according to claim 28, wherein the mixture of fatty acids and/or derivatives thereof is a mixture of unsaturated fatty acids and/or derivatives thereof.

30. The method according to claim 29, wherein the mixture of fatty acids and/or derivatives thereof is a mixture of polyunsaturated fatty acids and/or derivatives thereof.

31. The method according to claim 28, wherein the mixture of carboxylic acids and/or derivatives thereof is a mixture of cannabinoids and/or derivatives thereof.

32. The method according to claim 28, wherein the mixture containing a metabolite of a polyunsaturated fatty acid is a mixture containing a metabolite of eicosapentaenoic acid and/or of docosahexaenoic acid and/or of docosapentaenoic acid.

33. The method according to claim 28, wherein the at least one pre-resolving mediator and/or the specialized pre-resolving mediator is derived from EPA, DHA or/and from DPA.

34. The method according to claim 28, wherein in the mixture containing at least one pre-resolving mediator and/or specialized pre-resolving mediator, the pre-resolving mediator is 18-HEPE, 17-HDHA and/or 14-HDHA, and the specialized pre-resolving mediator is lipoxins, resolvins, protectins and/or maresins.

35. The method according to claim 18, wherein the target component is a polyunsaturated fatty acid or is cannabidiol or tetrahydrocannabinol.

36. The method according to claim 35, wherein the target component is eicosapentaenoic acid and/or docosahexaenoic acid.

37. The method according to claim 18, wherein the target component is a metabolite of a polyunsaturated fatty acid or is a substance having the same composition as the metabolite.

38. The method according to claim 37, wherein the target component is a metabolite of eicosapentaenoic acid and/or of docosahexaenoic acid and/or of docosapentaenoic acid.

39. The method according to claim 18, wherein the target component is a pre-resolving mediator and/or at least one specialized pre-resolving mediator.

40. The method according to claim 39, wherein the target component is at least one of the group consisting of 18-HEPE, 17-HDHA, 14-HDHA, lipoxin, resolvin, protectin and maresin.

41. A chromatography apparatus, comprising: at least one separating column for separating a starting material into fractions; a device for removing the fractions; a device for diverting off at least one of the fractions that has a defined target content of at least one target component of the starting material; and a conducting device for conducting at least a portion of the fractions that do not have the defined target content to the starting material yet to be separated.

42. The apparatus according to claim 41, wherein the conducting device is configured to conduct at least a portion of the fractions having a content of the target component that varies to a lesser degree from the defined target content than the target component content of the starting material to the starting material yet to be separated.

43. The apparatus according to claim 41, comprising a device configured to divert off at least the fractions in which the target component content varies to a greater degree from the defined target content than that of the starting material.

44. The apparatus according to claim 43, wherein the device configured to divert off at least the fractions in which the target component content varies to a greater degree from the defined target content than that of the starting material is configured to divert the fractions for further handling.

45. The apparatus according to claim 41, further comprising a device for measuring a content of the target component in the fractions.

46. The apparatus according to claim 45, further comprising a device for closed-loop and/or open-loop control of the fraction removal device, which is configured to use measurements ascertained by the measurement devices as controlled variables and/or manipulated variables for closed-loop and/or open-loop control.

Description

[0062] The invention is elucidated in detail hereinafter with reference to working examples and the appended drawings that relate to the working examples. The figures show:

[0063] FIG. 1 a schematic of an apparatus of the invention,

[0064] FIG. 2 a schematic of a portion of an apparatus of the invention according to FIG. 1, and

[0065] FIG. 3 a schematic of a further apparatus of the invention

A. APPARATUS ACCORDING TO FIGS. 1 AND 2

[0066] FIG. 1 shows a schematic of an inventive apparatus 1 for supercritical liquid chromatography. The apparatus 1 has the components, known per se, of an SFC apparatus as described, for example, in DE 199 34 168 A1. In particular, it comprises a separating column 5 which is charged with a starting material from a starting material reservoir 2 and an eluent from an eluent reservoir 4.

[0067] Fractions generated in the separation by means of separating column 5 are directed by means of a fractionation device 6 into fractionation columns 7, 8, 9. Each of the fractionation columns 7, 8, 9 is connected via conduits to a target product vessel 13, a residual material vessel 14 and a separation material vessel 3. In addition, each of the fractionation columns 7, 8, 9 has a switchable valve device 10, 11, 12, by means of which it is possible to establish the vessel into which the fractions that have been obtained in the respective fractionation columns 7, 8, 9 are directed. Consequently, by means of the switchable valve devices 10, 11, 12, it is possible to direct the respective fractions from the fractionation columns 7, 8, 9 electively into any of the vessels 3, 13, 14.

[0068] The separation material vessel 3 is fed with the starting material from the starting material reservoir 2. The material to be separated in the separating column 4 is fed out of the separation material reservoir 3.

[0069] The starting material reservoir 2 and the fractionation columns 7, 8, 9 and optionally the separation material vessel 3 are each provided with a measurement device 15, 16, 17, 18, 19, which is intended to determine the content of at least one component of a material in the respective container.

[0070] The apparatus 1 comprises a closed-loop control system 20 which, as shown schematically in FIG. 2, is set up to receive measurement data from the measurement device 15, 16, 17, 18, 19, and to use the measurement data to set the switchable valve devices 10, 11, 12.

[0071] In the case of performance of supercritical liquid chromatography, the separation vessel 3 is fed with starting material from the starting material reservoir 2, and the material from the separation vessel is separated in the separating column 5 by feeding in the eluent 4. The different fractions created are separated into the fractionation columns 7, 8, 9 by means of the fractionation device 6, and the content of a target product in the fractions is measured in the respective fractionation columns 7, 8, 9 by means of the measurement devices 15, 16, 17. In addition, the content of the target product is measured in the starting material reservoir 2 and optionally in the separation vessel 3 by means of the measurement devices 18, 19.

[0072] Conditions recorded in the closed-loop control system 20 are used as a reference for the setting of the valves of the valve devices 10, 11, 12.

[0073] A first condition is a minimum target product content. In the case of fractions having the defined minimum target product content according to the respective measurement, the valves are switched such that these fractions are directed into the target product vessel 13.

[0074] A further condition is that the target product content is less than the minimum target product content but greater than the target product content of the starting material, which is measured by means of measurement device 18. If a fraction from one of the fractionation columns 7, 8, 9 meets this condition, the fraction is fed into the separation vessel 3 and separated in the separating column 5 together with the as yet unprocessed starting material.

[0075] If one of the fractions from one of fractionation columns 7, 8, 9 meets none of the latter conditions, it is directed into the residual material vessel 14.

Example 1

[0076] In the above-described apparatus 1, starting material processed is an oil having 20% by weight of EPA and 70% by weight of DHA. This may be an oil that has been produced from fish oil or algae oil.

[0077] The aim of the processing by means of apparatus 1 is to obtain an oil having a DHA content of at least 90% by weight.

[0078] The oil to be processed is in the starting material reservoir 2.

[0079] The eluent provided in the eluent reservoir 4 is a mixture of CO.sub.2 with ethanol as cosolvent. After performance of the supercritical liquid chromatography, a fraction is formed in the fractionation column 7 that includes 68% by weight of DHA, a fraction is formed in the fractionation column 8 that includes 83% by weight of DHA, and a fraction is formed in the fractionation column 9 that contains 93% by weight of DHA.

[0080] In accordance with the measurement results, the valve devices 10, 11, 12 are set such that fraction from the fractionation column 7 that has a lower content of DHA than the starting material is directed into the residual material vessel 14. The valve device 11 is set such that the fraction from the fractionation column 8 which, at 83% by weight of DHA, has a smaller content than the target product content but a greater content than the content in the starting material is directed into the separation material vessel. The fraction from the fractionation column 9, at 93% by weight of DHA, has a DHA content greater than the minimum target product content of 90% by weight of DHA and is therefore directed into the target product vessel 3.

Example 2

[0081] Starting data as described above for example 1.

[0082] However, the fractions from the fractionation columns that do not meet the minimum target product content of 90% by weight of DHA are mixed with one another to give a residual material mixture, and the DHA content of the mixture is measured. If the residual material mixture has a DHA content greater than that of the starting material, it is introduced into the separation material vessel 3, where it is mixed with the starting material. If the DHA content of the residual material mixture is less than that of the starting material, it is directed into the residual material vessel 14.

Example 3

[0083] The above-described apparatus 1 is processed an oil as starting material, which has 20% by weight of EPA, 70% by weight of DHA and 4% by weight of arachidonic acid (ARA). This may be an oil which has been produced from fish oil or algae oil.

[0084] The aim of the processing by means of apparatus 1 is to obtain an oil having a DHA content of at least 90% by weight and an ARA content <0.5%.

[0085] The oil to be processed is present in the starting material reservoir 2.

[0086] The eluent provided in the eluent reservoir 4 is a mixture of CO.sub.2 with ethanol as cosolvent. After performance of the supercritical liquid chromatography, a fraction is formed in the fractionation column 7 that includes 66% by weight of DHA and 3.8% by weight of ARA, a fraction is formed in the fractionation column 8 that includes 83% by weight of DHA and 1.7% by weight of ARA, and a fraction is formed in the fractionation column 9 that contains 93% by weight of DHA and 0.3% by weight of ARA.

[0087] In accordance with the measurement results, the valve devices 10, 11, 12 are set such that fraction from the fractionation column 7 that has a lower content of DHA and a greater content of ARA than the starting material is directed into the residual material vessel 14. The valve device 11 is set such that the fraction from the fractionation column 8 which, at 83% by weight of DHA, has a smaller content for DHA than the target product content but a greater content than the content in the starting material and, at and 1.7% by weight of ARA, has a greater content for ARA than the target product content but a smaller content than the content in the starting material is directed into the separation material vessel. The fraction from the fractionation column 9, at 93% by weight of DHA, has a DHA content greater than the minimum DHA target product content of 90% by weight of DHA, and at 0.3% by weight of ARA, has an ARA content less than the maximum ARA target product content, and is therefore directed into the target product vessel 3.

Example 4

[0088] In the above-described apparatus 1, the starting material provided in the starting material reservoir is an oil including 72% by weight of EPA, 12% by weight of DHA and 16% by weight of SDA. This may be an oil that has been produced from fish oil or algae oil.

[0089] The eluent used, which is provided in the eluent reservoir 4, is a mixture of CO.sub.2 with ethanol as cosolvent. Contents of EPA, DHA and SDA are determined by means of the measurement device 15, 16, 17, 18, 19, and settings are accordingly as elucidated above.

[0090] The aim of the processing by means of apparatus 1 is to obtain an oil having an EPA content of at least 96% by weight. A fraction with such an EPA content is introduced into target product vessel 13.

[0091] Additionally directed into the separation material vessel 3 are fractions having <96% by weight of EPA but ?75% by weight of EPA, <3% by weight of DHA and <6% by weight of SDA.

[0092] Fractions having none of the aforementioned contents are introduced into the residual material vessel 14.

Example 5

[0093] The above-described apparatus 1 is processed an oil as starting material, which includes 70% by weight of CBD. This may be an extract that has been produced from hemp.

[0094] The aim of the processing by means of apparatus 1 is to obtain an oil having a CBD content of at least 90% by weight.

[0095] The oil to be processed is present in the starting material reservoir 2.

[0096] The eluent provided in the eluent reservoir 4 is a mixture of CO.sub.2 with ethanol as cosolvent. After performance of the supercritical liquid chromatography, a fraction is formed in the fractionation column 7 that includes 63% by weight of CBD, a fraction is formed in the fractionation column 8 that includes 87% by weight of CBD, and a fraction is formed in the fractionation column 9 that contains 95% by weight of CBD.

[0097] In accordance with the measurement results, the valve devices 10, 11, 12 are set such that fraction from the fractionation column 7 that has a lower content of CBD than the starting material is directed into the residual material vessel 14. The valve device 11 is set such that the fraction from the fractionation column 8 which, at 87% by weight of CBD, has a smaller content than the target product content but a greater content than the content in the starting material is directed into the separation material vessel. The fraction from the fractionation column 9, at 95% by weight of CBD, has a CBD content greater than the minimum target product content of 90% by weight of CBD and is therefore directed into the target product vessel 3.

B. APPARATUS ACCORDING TO FIG. 3

[0098] FIG. 3 shows a schematic of a further inventive apparatus 1a. For separation of a substance mixture, the apparatus 1a has a chromatography device 5a suitable for performance of simulated moving bed (SMB) chromatography. The chromatography device 5a has two or more separating columns connected to one another that collectively form zones I, II, III, IV. As known per se for SMB methods, the chromatography device 5a is supplied at varying points with the substance mixture to be separated and an eluent, and a raffinate and an extract are likewise withdrawn at varying points.

[0099] For this purpose, a directing device 27 is provided, comprising suitable conduits and valves and optionally connections, and a device for setting the valves. The directing device 27 may also have at least one pump, preferably two or more pumps, in order to provide the possibility of acting on material flows in the conduits.

[0100] In order to feed the chromatography device 5a with the substance mixture to be separated, the apparatus 1a has a separation material vessel 3a connected to a starting material reservoir 2a in which the starting material to be separated is disposed. Raffinate removed by means of the chromatography device 5a is directed into a raffinate vessel 21, and removed extract into an extract vessel 22. Before the raffinate and the extract are directed into the respective vessels 21, 22, the eluent may be separated respectively from the raffinate and from the extract, especially by evaporation, in separation devices 23, 24. The separation devices 23, 24 may be formed, for example, by a falling-film evaporator. The eluent from the separation devices 23, 24 may be recycled into an eluent reservoir.

[0101] Depending on the target product content(s), the raffinate is directed into a target product vessel 13a or, for the purpose of recycling, into the separation material vessel 3a. The extract, likewise depending on the target product content, is introduced into the separation material vessel 3a or into a residual material vessel 14a.

[0102] The substance mixture from the separation material vessel 3a, formed by a mixture of the starting material fed in via the starting material reservoir 2a and optionally of raffinate and/or extract, is then introduced the chromatography device 5a. There is continuous separation of material therein.

[0103] As FIG. 3 shows, the chromatography device 5a is connected via the directing device 27 to the raffinate vessel 21, the extract vessel 22, the residual material vessel 14a and the separation material vessel 3a.

[0104] As can be inferred from FIG. 3, a measurement device 19a is provided for the separation material vessel 3a, a measurement device 25 for the raffinate vessel 21, and a measurement device 26 for the extract vessel, by means of which the target product content(s) of the substances disposed in each can be measured. In addition, the starting material reservoir 2a may be provided with a measurement device 18a for determination of the product content or target product contents.

[0105] In an analogous manner to that elucidated above with reference to FIGS. 1 and 2, the apparatus 1a may have a closed-loop and/or open-loop control device 20a which takes account of the measurement values ascertained by the measurement devices 19a, 25, 26 and optionally 18a to establish how the substance mixture is formed in separation material vessel 3a by mixing the starting material, the raffinate and the extract, and/or how much of the substance mixture is fed to the chromatography device 5a. It will be apparent that the closed-loop and/or open-loop control device 20a is set up such that it can adjust the directing device 27, especially the valves and any pumps thereof.

Example 6

[0106] In the above-described apparatus 1, the starting material processed is an oil having 60% by weight of EPA, 15% by weight of DHA and 10% by weight of ARA. This may be an oil that has been produced from fish oil or algae oil. The aim of processing by means apparatus 1 is to obtain an oil having a DHA content of at least 90% by weight.

[0107] The oil to be processed is present in the starting material reservoir 2.

[0108] The eluent used, which is provided in the eluent reservoir 4, is ethanol.

[0109] In the course of continuous substance separation by means of the chromatography device 5a by the SMB method, the raffinate removed is a substance mixture having an EPA content that varies between 86% by weight and 97.5% by weight.

[0110] The closed-loop and/or open-loop control device 20a is programmed such that the raffinate is directed into the target product vessel 13a when the EPA content is >90% by weight, and into the separation material vessel when the EPA content is <90% by weight.

[0111] In addition, the closed-loop and/or open-loop control device 20a is programmed such that the extract is directed into the separation material vessel when the EPA content is >70% by weight and the ARA content is <10% by weight, and is otherwise directed into the residual material vessel 14a.

[0112] The closed-loop and/or open-loop control device 20a may also be provided such that the amount of molar amounts respectively introduced into the separation material vessel 3a from the starting material reservoir 2a, the raffinate vessel 21 and the extract vessel are adjusted such that the respective contents of EPA, DHA and ARA are within a certain defined range.