CN108640840A - A kind of the multicolumn continuous chromatography method and equipment of purifying eicosapentaenoic acid ethyl ester - Google Patents
A kind of the multicolumn continuous chromatography method and equipment of purifying eicosapentaenoic acid ethyl ester Download PDFInfo
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Abstract
The present invention provides a kind of purifying eicosapentaenoic acid ethyl ester（Eicosapentaenoic acid, EPA EE）Chromatographic process and equipment, it is characterised in that：Described to be equipped for multicolumn continuous chromatography system, which is divided into Liang great Qu：Crude separation area and smart Disengagement zone；Crude separation area is made of five subprovinces：Smart Disengagement zone is made of two subprovinces：Each subprovince by 1~nBranch Coupled columns are constituted；Chromatographic process on the equipment is：The sample of the EE containing EPA is in I area's Pulsed Sampling；It is miscellaneous before IIth area removes（EPA EE are eluted to and just penetrate IIth area）；EPA EE are eluted to just completely into IV area end column in IVth area；It is finely detached in VIth area（EPA EE are eluted to and just penetrate VIth area）；Fractional Collections EPA EE are eluted in VIIth area and containing a small amount of rear miscellaneous EPA EE；It is miscellaneous after III and V area removes.The above method is realized by intelligent controls such as valve transfer, the start and stop of pump or/and flow velocity regulation and control.
Description
Technical field
The present invention relates to a kind of purifying eicosapentaenoic acid ethyl ester (Eicosapentaenoic acid ethyl ester,
EPA-EE chromatographic process) and equipment, the more particularly to a kind of method and its equipment of multicolumn continuous chromatography.
Background technology
EPA is the precursor of a variety of important biomolecule molecules, has and adjusts the various biologicals such as platelet aggregation, inflammation, immune
Function, for nerve center, neurological disease, angiocardiopathy, immunity disease, diseases associated with inflammation, including rheumatoid joint
Inflammation, the great treatment foreground of the diseases such as inflammatory bowel disease, Alzheimer disease, Parkinson's disease, metabolic syndrome and tumour.
EPA-EE in 2013 is approved by the FDA in the United States listing as blood lipid-lowering medicine.
EPA is mainly derived from fish oil.In fish oil other than EPA, also contain docosahexaenoic acid, docosapentaenoic
A variety of aliphatic acid such as acid, parinaric acid, linoleic acid, oleic acid, stearic acid and palmitic acid, since molecular structure is similar, physics and chemistry
Property is close, these non-EPA aliphatic acid can interfere the therapeutic effect of EPA-EE.Therefore, the demand of high-purity EPA E and day
It is all to increase.
The technological core for preparing EPA-EE is batch and cost.The challenge for preparing EPA-EE is：1, aliphatic acid coexists
Structure and physicochemical property are close with EPA-EE；2, the stability of EPA-EE is poor, in preparation process easy isomerization, oxidation or/and
Degradation.
Currently, the disclosed main method urea adduct crystallisation (United States Patent (USP) 6664405) for preparing EPA-EE, gold
Belong to salt precipitation method (United States Patent (USP) 6846942) and molecularly distilled (United States Patent (USP) 8889895), the market demand cannot be provided
High-purity EPA E.
Orochem Technologies companies in 2014 disclose method (U.S. that SMB three times prepares high-purity EPA E
State's patent 9163198), the first chromatography is positive SMB in this method, and second and third time chromatography are reverse phase SMB.2016
BASF AG discloses the method (United States Patent (USP) 9695382) that reverse phase SMB three times prepares high-purity EPA E.
Although the method that United States Patent (USP) 9163198 and 9695382 is provided can prepare the EPA-EE of content >=97%, by
In in all separating and purifying technologies, chromatography is that minimum production capacity, cost highest, operator quality requirement are high, operation is fine,
The cost of time-consuming, effort technology, the high-purity EPA E that SMB methods are provided three times is difficult to be widely accepted.
In conclusion medical market active demand is of large quantities, the preparation method of high-purity EPA E at low cost.
Invention content
In view of the above-mentioned problems, the purpose of the present invention is to provide a kind of systems of high-purity EPA E of large quantities, at low cost
Preparation Method and equipment.
To achieve the above object, the present invention is equipped using following chromatographies：It is synchronized and is cut by branched shorter chromatogram column, 1 multithread road
Valve, 7 constant flow pumps, 2 UV detector and 1 fraction collector structure continuous chromatography system are changed, it is big which is divided into two
Area：Crude separation area and smart Disengagement zone.Crude separation area is made of five subprovinces：Loading area, the areas Qu Qianza, 1st areas Qu Houza, EPA-
The elution zones EE, 2nd areas Qu Houza, are defined as I, II, III, IV and V area successively.Smart Disengagement zone is made of two subprovinces：Essence separation
Area and the elution zones EPA-EE are defined as VI and VII area successively.Subprovince is by 1~n (n=1,2,3,4,5,6 or 7) branch chromatographic column string
Connection is constituted.Chromatographic process on the equipment is：Sample containing EPA-EE is in I area's Pulsed Sampling；After single injected sampling, cut through valve
It changes, I area end column carry is II area's head columns, before IIth area removes miscellaneous (be eluted to EPA-EE and just penetrate IIth area)；It is cut through valve
It changes, II area end column carry is IV area's head columns, and EPA-EE is eluted to just completely into IV area end column in IVth area；In III and V
Area is miscellaneous after removing；Through valve transfer, IV area end column carry is VI area's head columns, and sample carries out finely separation (by EPA-EE in VIth area
It is eluted to and just penetrates VIth area)；Through valve transfer, VI area end column carry is VII area's head columns, in VIIth area elution Fractional Collections EPA-EE
With contain it is a small amount of after miscellaneous EPA-EE；The above method passes through the intelligent controls such as valve transfer, the start and stop of pump or/and flow velocity regulation and control
It realizes.
In the above method provided by the present invention and its equipment, using the chromatographic column of same geometric dimension：Chromatographic column is straight
Diameter is 10~2000mm, and column diameter size directly determines the height of production capacity；Chromatogram column length is 50~300mm, most short column
Length should be able to accommodate target compound all in an applied sample amount.
In the above method provided by the present invention and its equipment, the chromatographic column can all load C18Reverse phase silica gel, silica gel
5~40 μm of grain size.
In the above method provided by the present invention and its equipment, frequency and the valve transfer frequency phase of the Pulsed Sampling
Deng sample introduction is primary, and switching is primary, or switching is primary, and sample introduction is primary.
In the above method provided by the present invention and its equipment, raw material to be separated (weight hundred containing EPA-EE 30~90%
Divide ratio).
In the above method provided by the present invention and its equipment, sample concentration is containing 50~90% (weight of raw material to be separated
Percentage) methanol solution.
In the above method provided by the present invention and its equipment, the methanol-water that the mobile phase in each area is 95~100% is eluted
Solution, 3~5cm/min of flow rate of mobile phase.
In the above method provided by the present invention and its equipment, the switching of valve is controlled automatically by the detected value of VI area's detector
System.
In the above method provided by the present invention and its equipment, Ith area is automatically controlled by the timing start and stop of I area's constant flow pump
Applied sample amount；The elution terminal in Ith area is automatically controlled by the start and stop of detected value II area's constant flow pump of countercharge of II area's detector；Pass through
III, the timing start and stop of IV, V or VII area's constant flow pump automatically control the elution terminal in III, IV, V or VII area；It is collected by VIIth area
The exchange-column shift of device automatically controls EPA-EE and is collected containing rear miscellaneous EPA-EE；Control each area's constant flow pump start and stop and collector switching
Time by experiment obtain.
The invention adopts the above technical scheme, which has the following advantages：1, the EPA-EE containing a large amount of pre-impurity and post-impurity
Raw material is finely detached after a large amount of pre-impurity and post-impurity of crude separation area removing, then through smart Disengagement zone, is thus greatly reduced
Smart Disengagement zone chromatography load and total peak width enhance chromatogram separating capacity, improve sample introduction frequency, improve production capacity；2、
Each chromatographic process of crude separation area and smart Disengagement zone is carried out at the same time in respectively different subprovinces, further reduced chromatographic process
Required time improves production capacity.
The present invention provides the stronger multicolumn of a kind of sample introduction frequency higher, separating capacity to prepare high-purity EPA E and connects
Continuous chromatographic process and equipment, can further improve production capacity, reduce cost, it is urgent to high-purity EPA E can to meet medical market
Demand.
Description of the drawings
Fig. 1 is the structure of method provided by the present invention and its equipment and the principle schematic of chromatographic process；
Fig. 2 is that the embodiment of the present invention two prepares chromatogram；
Fig. 3 is the constituent analysis figure for preparing chromatogram of the embodiment of the present invention two；
Fig. 4 is that the embodiment of the present invention three prepares chromatogram；；
Fig. 5 is the constituent analysis figure for preparing chromatogram of the embodiment of the present invention three；
Fig. 6 is the monitoring figure of one II area's detector of the embodiment of the present invention；
Fig. 7 is the monitoring figure of one IV area's detector of the embodiment of the present invention；
Fig. 8 is method provided by the present invention and its another structure of equipment and its principle schematic of chromatographic process；
Specific implementation mode
The present invention is described in detail below with reference to the accompanying drawings and embodiments.
Embodiment one
As shown in Figure 1, the change system that the present embodiment is provided is by 1 12 column, 7 flow path rotary valve, 12 chromatographic columns
(20mm ID×100mm,C18Reverse phase silica gel, 10 μm, column effect >=4000), 7 constant flow pumps (1~50ml/min), 2 ultraviolet inspections
Device and 1 segmentation collector structure are surveyed, which is divided into Liang great Qu：Crude separation area and smart Disengagement zone.Crude separation area is by five
Subprovince forms：Loading area (No. 1 column), the areas Qu Qianza (2 and No. 4 columns), 1st areas Qu Houza (No. 3 columns), sample elution area (5 and No. 7
Column), 2nd areas Qu Houza (No. 6 columns), be defined as I, II, III, IV and V area's (dotted line frame) successively.Smart Disengagement zone is by two subprovince groups
At：Smart Disengagement zone (8,9,10 and No. 11 columns) and sample elution area (No. 12 columns), are defined as VI and VII area successively.7 pumps are independent
Convey multigroup part of sample liquid F and 6 kinds of mobile phase S2~S7.The II column outlet end of area 4 is connected with UV detector, and detector is examined
The signal strength control mobile phase S measured2The start and stop of solution feed pump.The VI column outlet end of area 11 and UV detector phase
Even, the switching of the signal strength control rotary valve detected by detector.I, III, IV, V or VII area's constant flow pump is timing start and stop
Control.The VII column outlet end of area 12 is connected with fraction collector, and collector is controlled using exchange-column shift.
Chromatography processes parameter in the present embodiment system is：Raw material to be separated contains EPA-EE 70%；Sample introduction concentration
500mg/ml；6 kinds of mobile phase S2~S7It is identical, it is 95% methanol aqueous solution；I area's constant current flow rate pump is 5 ml/min, sample introduction
Time 1min；II~VII area's constant current flow rate pump is identical, is 15ml/min；Detection wavelength 210nm；II area's termination of pumping peak value 940mV
(constant flow pump run time about 9.2min)；IV area rotary valve switch peak value V870mV (constant flow pump run time 16.3min)；Ⅲ
It is 12min with V area's constant flow pump run time；IV area's constant flow pump run time is 5.4min；VII area's constant flow pump run time is
15min, 0~4min of fraction collector switching time 4min, EPA-EE acquisition time.9.2+5.4+12+12+16.3+15
Chromatographic process in the present embodiment system is：The sample F of 500mg/ml in I area's Pulsed Sampling, sample introduction frequency with
Valve transfer frequency is equal, and sample introduction is primary, and switching is primary；After single injected sampling, through valve transfer, the I column carry of area 1 is II area 2
Number column, in IIth area by mobile phase S2Elution, the pump trip (Fig. 6) when II area's detected value reaches 940mV；Through valve transfer, IIth area
No. 4 column carries are the column of IVth area 5, in IVth area by mobile phase S4Elute 5.4min pump trips；Through valve transfer, IV column of area 7
Carry is the column of VIth area 8, in VIth area by mobile phase S6Elution, when VI area's detected value reaches 870mV, rotary valve automatically switches (figure
7)；When rotating Vavle switching, I~VII area's constant flow pump is wholly off；Through valve transfer, the VI column carry of area 11 is the column of VIIth area 12,
In VIIth area by mobile phase S7Elution, 0~4min collect EPA-EE, and fraction collector automatically switches when 4min.It is distinguished III and V
Not by mobile phase S3With mobile phase S5Each elution 12min is miscellaneous after removing.Above process automatic cycle carries out, and time course refers to table
1.It the results are shown in Table 2.
The time course of 1 system of table
The process conditions of two embodiment one of embodiment confirm experiment
The change system that the present embodiment is provided is by 2 chromatographic columns (20mm ID × 100mm, C18Reverse phase silica gel, 10 μm,
Column effect >=4000), 2 constant flow pumps (1~50ml/min), 1 UV detector and 1 segmentation collector structure：2 colors
Spectrum column is used in series, and 2 parallels connection of pumps use, and 1 is used for sample introduction, and another for eluting.Chromatography work in the present embodiment system
Skill parameter is：Raw material to be separated contains EPA-EE 70%；Sample introduction concentration 500mg/ml；The methanol aqueous solution that mobile phase is 95%.
Chromatographic process in the present embodiment system is：The sample of 500mg/ml is with 5ml/min flow velocity sample introductions 1min；With
95% methanol aqueous solution is eluted sample with 15ml/min flow velocitys completely, is collected simultaneously device Fractional Collections whole chromatographic peak, and
Analyze each section of eluate ingredient.As a result as shown in Figures 2 and 3.According to the present embodiment as a result, IIth area in embodiment one is stopped
Pump peak value is set to 940mV, and the run time of IV area's constant flow pump is set to 5.4min.
The process conditions of three embodiment one of embodiment confirm experiment
The change system that the present embodiment is provided is by 6 chromatographic columns (20mm ID × 100mm, C18Reverse phase silica gel, 10 μm,
Column effect >=4000), 2 constant flow pumps (1~50ml/min), 1 UV detector and 1 segmentation collector structure：2 and 4
Branch chromatographic column is connected respectively, and 2 parallels connection of pumps use, and 1 is used for sample introduction, and another for eluting.Color in the present embodiment system
Composing technological parameter is：Raw material to be separated contains EPA-EE 70%；Sample introduction concentration 500mg/ml；The methanol that mobile phase is 95% is water-soluble
Liquid.
Chromatographic process in the present embodiment system is：The sample of 500mg/ml is with 2 series connection colors of 5ml/min flow velocitys sample introduction
Compose column 1min；Peak value is eluted to 15ml/min flow velocitys with 95% methanol aqueous solution and reaches 940mV terminations of pumping；No. 1 column is removed, by 2
Number column is connected respectively with another 4 chromatographic columns；Continue to be washed sample completely with 15ml/min flow velocitys with 95% methanol aqueous solution
It is de-, it is collected simultaneously device Fractional Collections whole chromatographic peak, and analyze each section of eluate ingredient.As a result as shown in Figure 4 and Figure 5.According to
The present embodiment by VI area peak value 870mV in embodiment one as a result, be set to rotary valve switching command, when VII area EPA-EE is collected
Between be set to 4min.
Example IV single column chromatographic comparative experiments
The change system that the present embodiment is provided is by 6 chromatographic columns (20mm ID × 100mm, C18Reverse phase silica gel, 10 μm,
Column effect >=4000), 2 constant flow pumps (1~50ml/min), 1 UV detector and 1 segmentation collector structure：6 colors
Spectrum column is connected respectively, and 2 parallels connection of pumps use, and 1 is used for sample introduction, and another for eluting.Chromatography work in the present embodiment system
Skill parameter is：Raw material to be separated contains EPA-EE 70%；Sample introduction concentration 500mg/ml；The methanol aqueous solution that mobile phase is 95%.
Chromatographic process in the present embodiment system is：The sample of 500mg/ml is with 5ml/min flow velocity sample introductions 1min；With
95% methanol aqueous solution is eluted sample with 15ml/min flow velocitys completely, is collected simultaneously device Fractional Collections whole chromatographic peak, and
Analyze each section of eluate ingredient.It the results are shown in Table 2.
The comparison of table 2 multicolumn continuous chromatography and single column chromatographic
Embodiment five
As shown in figure 8, the change system that the present embodiment is provided is by 1 10 column, 7 flow path rotary valve, 11 chromatographic column (its
In 10 chromatographic columns be 200mm ID × 100mm, C18Reverse phase silica gel, 10 μm, column effect >=4000；Another chromatographic column is 200mm
ID×200mm,C18Reverse phase silica gel, 10 μm, column effect >=8000), 7 constant flow pumps (1~50ml/min), 2 UV detector and
1 segmentation collector structure, the system are divided into Liang great Qu：Crude separation area and smart Disengagement zone.Crude separation area is by five subprovince groups
At：Loading area (No. 1 column), 1st areas Qu Houza (No. 3 columns), sample elution area (5 and No. 7 columns), is gone the areas Qu Qianza (2 and No. 4 columns)
2nd areas Hou Za (No. 6 columns), are defined as I, II, III, IV and V area's (dotted line frame) successively.Smart Disengagement zone is made of two subprovinces：Essence
Disengagement zone (8,9 and No. 10 columns) and sample elution area (No. 11 columns), are defined as VI and VII area successively.The independent conveying of 7 pumps is multigroup
Part sample liquid F and 6 kinds of mobile phase S2~S7.The II column outlet end of area 4 is connected with UV detector, detected by detector
Signal strength controls mobile phase S2The start and stop of solution feed pump.The VI column outlet end of area 11 is connected with UV detector, detection
The switching of signal strength control rotary valve detected by device.I, III, IV, V or VII area's constant flow pump is timing start-up and shut-down control.Ⅶ
The column outlet end of area 12 is connected with fraction collector, and collector is controlled using exchange-column shift.
Chromatographic process in the present embodiment system is identical as embodiment one.
In the present embodiment, 2 100mm long chromatographic columns in embodiment one are merged into 1 200mm long chromatographic column, and will
It is arranged outside rotary valve, the diameter of rotation can be reduced, to reduce equipment cost.
The present invention is only illustrated with above-described embodiment, the structure of equipment provided by the present invention and the embodiment party of chromatographic process
Method may be changed.Based on the technical solution of the present invention, it is all according to the principle of the invention to equipment structure and real
The improvement or equivalents that applying method carries out, should not exclude except protection scope of the present invention.
Claims (10)
1. a kind of purifying eicosapentaenoic acid ethyl ester（Eicosapentaenoic acid, EPA-EE）Chromatographic process and equipment,
It is characterized in that：Described to be equipped for multicolumn continuous chromatography system, the system is divided into Liang great Qu：Crude separation area and smart Disengagement zone；
The crude separation area is made of five subprovinces：Loading area, the areas Qu Qianza, 1st areas Qu Houza, sample elution area, 2nd areas Qu Houza, according to
It is secondary to be defined as I, II, III, IV and V area；The essence Disengagement zone is made of two subprovinces：Smart Disengagement zone and sample elution area, successively
It is defined as VI and VII area；The subprovince by 1~n（n=1,2,3,4,5,6 or 7）Branch Coupled columns are constituted；On the equipment
Chromatographic process be：The raw material to be purified containing EPA-EE is dissolved in methanol and is prepared into loading sample；Sample is in I area's Pulsed Sampling；Once
After sample introduction, through valve transfer, I area end column carry is II area's head columns, miscellaneous before IIth area removes（EPA-EE is eluted to and just penetrates II
Area）；Through valve transfer, II area end column carry is IV area's head columns, and EPA-EE is eluted to just completely into IVth area end in IVth area
Column；It is miscellaneous after III and V area removes；Through valve transfer, IV area end column carry is VI area's head columns, and sample is finely divided in VIth area
From（EPA-EE is eluted to and just penetrates VIth area）；Through valve transfer, VI area end column carry is VII area's head columns, elutes and is segmented in VIIth area
Collect EPA-EE and containing a small amount of rear miscellaneous EPA-EE；The above method passes through valve transfer, the start and stop of pump or/and flow velocity regulation and control etc.
Intelligent control is realized.
2. the method as described in claim 1 and its equipment, it is characterised in that：The chromatographic column is all same geometric dimension, directly
Diameter is 10~2000mm, and length is 50~300mm.
3. the method as described in claim 1 and its equipment, it is characterised in that：The chromatographic column all loads C18Reverse phase silica gel, silicon
5~40 μm of micelle diameter.
4. the method as described in claim 1 and its equipment, it is characterised in that：The raw material to be separated contains EPA-EE 30~90%
（Weight percent）.
5. the method as described in claim 1 and its equipment, it is characterised in that：The a concentration of of the loading sample contains original to be separated
Material 50~90%（Weight percent）Methanol solution.
6. the method as described in claim 1 and its equipment, it is characterised in that：The mobile phase in each area is all 95~100%
Methanol aqueous solution.
7. the method as described in claim 1 and its equipment, it is characterised in that：II~VII area mobile phase elution flow rate is 3
~6cm/min.
8. the method as described in claim 1 and 6 and its equipment, it is characterised in that：The switching of the rotary valve is detected by VIth area
The detected value of device automatically controls.
9. the method as described in claim 1 and its equipment, it is characterised in that：The elution terminal in IIth area is by II area's detector
Detected value countercharge.
10. the method as described in claim 1 and its equipment, it is characterised in that：The applied sample amount in Ith area and III, IV, V or VII
The elution terminal in area and VII area's collector switching are timing automatic control.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111841073A (en) * | 2019-09-12 | 2020-10-30 | 浙江大学宁波理工学院 | Multi-column switching cycle chromatographic separation system and method for separating and concentrating target components from raw materials |
| CN113831244A (en) * | 2020-06-24 | 2021-12-24 | 北京创新通恒科技有限公司 | Separation equipment and process method for purifying high-purity EPA-ee |
| CN114685266A (en) * | 2020-12-25 | 2022-07-01 | 北京创新通恒科技有限公司 | Separation equipment and process method for purifying high-purity EPA-ee from fish oil |
| CN115015458A (en) * | 2022-07-01 | 2022-09-06 | 江苏汉邦科技股份有限公司 | Split-flow chromatography system and method for preparing ethyl eicosapentaenoate by using split-flow chromatography system |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107185273A (en) * | 2017-06-15 | 2017-09-22 | 苏州麦可旺志生物技术有限公司 | The method and its equipment of a kind of continuous chromatography |
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- 2017-12-13 CN CN201711329373.3A patent/CN108640840B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107185273A (en) * | 2017-06-15 | 2017-09-22 | 苏州麦可旺志生物技术有限公司 | The method and its equipment of a kind of continuous chromatography |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111841073A (en) * | 2019-09-12 | 2020-10-30 | 浙江大学宁波理工学院 | Multi-column switching cycle chromatographic separation system and method for separating and concentrating target components from raw materials |
| CN113831244A (en) * | 2020-06-24 | 2021-12-24 | 北京创新通恒科技有限公司 | Separation equipment and process method for purifying high-purity EPA-ee |
| CN114685266A (en) * | 2020-12-25 | 2022-07-01 | 北京创新通恒科技有限公司 | Separation equipment and process method for purifying high-purity EPA-ee from fish oil |
| CN115015458A (en) * | 2022-07-01 | 2022-09-06 | 江苏汉邦科技股份有限公司 | Split-flow chromatography system and method for preparing ethyl eicosapentaenoate by using split-flow chromatography system |
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