CN113831244A - Separation equipment and process method for purifying high-purity EPA-ee - Google Patents
Separation equipment and process method for purifying high-purity EPA-ee Download PDFInfo
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- CN113831244A CN113831244A CN202010600205.9A CN202010600205A CN113831244A CN 113831244 A CN113831244 A CN 113831244A CN 202010600205 A CN202010600205 A CN 202010600205A CN 113831244 A CN113831244 A CN 113831244A
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Abstract
The invention discloses a separation device and a process method for purifying high-purity EPA-ee. Primary purification: putting a fish oil raw material containing 70% of EPA-ee content into a preparation bottle to prepare a preparation solution, taking the preparation solution as a sample loading solution 1 to carry out continuous sample loading, separating through a separation equipment body and a chromatographic column, continuously separating, and removing EPA-ee post-impurities to obtain an intermediate product without post-impurities; after the sample solution 1 is purified into a product, concentrating the product into methanol-free water without diluting the product to be used as a sample solution 2; and (3) secondary purification: the intermediate product was used as a sample solution 2 to carry out continuous sampling. Has the advantages that: the chromatographic purification process is used for one-step purification, so that a 97% intermediate product can be obtained, and the intermediate product is purified in a two-step manner, so that an EPA product with the purity of more than 99% can be obtained; in a word, the super-chromatographic purification process has the advantages of low production cost, good product quality, high EPA yield and environmental friendliness, and is beneficial to industrial production.
Description
Technical Field
The invention relates to a process method for purifying high-purity EPA-ee, in particular to separation equipment and a process method for purifying high-purity EPA-ee.
Background
At present, fish oil extract medicines approved in China are lipid regulators, have the effects of reducing serum triglyceride and total cholesterol, are used for hyperlipidemia, and comprise eicosapentaenoic acid ethyl ester (hereinafter referred to as EPA-ee) as an active ingredient. However, due to the limitation of process technology, most of the fish oil polyenoic acid ethyl ester medicines in the market have poor quality, low purity and unstable impurities, so that the curative effect is not ideal, even some adverse reaction cases occur, and the difference between the medicines and international main products is large.
The traditional chromatography process mainly has the following problems:
1. because unsaturated fatty acid components are complex and have more components similar to chemical components of EPA, if the sample loading amount is high, the EPA purity is not high, and related impurities are remained, the preparation and purification are required for two times, even three times and four times, but the preparation times are more, the total yield is lower, and the production cost is higher; the sample loading amount is small, the obtained EPA has high purity, but the unit filler, the unit solvent and the unit time treatment amount are small, and the production cost is high.
2. The collected fractions to be detected are more in sections, the detection pressure is high before the qualified products are combined, the number of collecting tanks needs to be increased for reducing the waiting time for detecting the fractions in the previous batch in the production of the preparation column, and detection personnel and detection equipment are added, so that the production cost is increased.
Therefore, a purification scheme with high purity of the prepared product and low production cost is urgently needed to be developed so as to meet the requirement of industrial development.
An effective solution to the problems in the related art has not been proposed yet.
Disclosure of Invention
The invention aims to provide separation equipment and a process method for purifying high-purity EPA-ee, which aim to solve the problems in the background technology.
Therefore, the invention adopts the following specific technical scheme:
according to an aspect of the present invention, there is provided a separation apparatus for purifying high purity EPA-ee.
The high-purity EPA-ee purification separation equipment comprises a placing seat, wherein a separation equipment body, a plurality of chromatographic columns and a plurality of preparation bottles are arranged on the placing seat.
According to another aspect of the present invention, there is provided a process for purifying high purity EPA-ee separation device, comprising the steps of;
firstly, purifying the EPA content in the raw material to more than 70% by molecular distillation, and directly using fish oil with 70% of EPA-ee content as the raw material;
primary purification: putting a fish oil raw material containing 70% of EPA-ee content into a preparation bottle to prepare a preparation solution, taking the preparation solution as a sample loading solution 1 to carry out continuous sample loading, separating through a separation equipment body and a chromatographic column, continuously separating, and removing EPA-ee post-impurities to obtain an intermediate product without post-impurities;
after the sample solution 1 is purified into a product, concentrating the product into methanol-free water without diluting the product to be used as a sample solution 2;
and (3) secondary purification: continuously loading the sample by taking the intermediate product as a sample loading liquid 2, continuously separating by using a separation equipment body and a chromatographic column, and removing EPA-ee precursor impurities to obtain a high-purity EPA-ee monomer;
fish oil with 70% of EPA-ee content in the sample loading liquid 1 is not diluted;
the EPA-ee content of the sample liquid 2 is 97 percent, namely the EPA-ee concentration of a pure product concentrated solution is 0.97 mg/mL.
Further, the flow rate of high-concentration methanol in one purification is 1800mL/min, the flow rate of 92% methanol-water (volume ratio) is 1710mL/min, and the sample loading flow rate is 6.75 mL/min. The density of the sample solution 1 is 1mg/mL, namely the concentration of EPA-ee in the sample solution 1 is 0.7 mg/mL; thus, 1 pure high methanol dosage of 1800mL per minute, EPA-ee dosage of 4.725mg per minute was processed.
Further, in the second purification, 92% methanol-water (volume ratio) flow was 2070mL/min, sample flow was 5.625mL/min, 92% methanol-water (volume ratio) use amount was 2070mL/min, EPA-ee amount was processed 5.45625 mg/min, EPA-ee purity was 99%.
Further, the stationary phase of the chromatographic column is C18, and the height of the chromatographic column is only 200 mm.
Further, the mobile phase of the primary purification and the secondary purification is 92% ethanol water.
The invention provides separation equipment and a process method for purifying high-purity EPA-ee, which have the following beneficial effects:
(1) the chromatographic process in the scheme only uses a methanol aqueous solvent, only one methanol proportion is used for purification, only one methanol proportion is used for regeneration, and the recovery and the application are simple;
(2) the reversed phase silica gel filler used by the separation equipment has good separation effect, simple GMP/FDA certification, reusability and small environmental pollution; the chromatographic column purification process has high filler utilization rate, large unit filler raw material treatment capacity per unit time, high productivity and small unit product methanol use amount;
(3) the chromatographic purification process is used for one-step purification, so that a 97% intermediate product can be obtained, and the intermediate product is purified in a two-step manner, so that an EPA product with the purity of more than 99% can be obtained; in a word, the super-chromatographic purification process has the advantages of low production cost, good product quality, high EPA yield and environmental friendliness, and is beneficial to industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 is a schematic configuration diagram of a separation apparatus for purifying high-purity EPA-ee according to an embodiment of the present invention;
FIG. 2 is a diagram showing a distribution of a primary purification asynchronous switching time and regions in a process for purifying a high purity EPA-ee separation apparatus according to an embodiment of the present invention;
FIG. 3 is a graph of the asynchronous switching time and zones for the secondary purification in a process for purifying a high purity EPA-ee separation device according to an embodiment of the present invention;
FIG. 4 is a table of peaks of one purification in a process for purifying a high purity EPA-ee separation device according to an embodiment of the present invention;
fig. 5 is a table showing peaks of secondary purification in a process for purifying a high-purity EPA-ee separation device according to an embodiment of the present invention.
Reference numerals:
1. a placing seat; 2. a separation device body; 3. a chromatographic column; 4. a bottle was prepared.
Detailed Description
For further explanation of the various embodiments, the drawings which form a part of the disclosure and which are incorporated in and constitute a part of this specification, illustrate embodiments and, together with the description, serve to explain the principles of operation of the embodiments, and to enable others of ordinary skill in the art to understand the various embodiments and advantages of the invention, and, by reference to these figures, reference is made to the accompanying drawings, which are not to scale and wherein like reference numerals generally refer to like elements.
According to the embodiment of the invention, the separation equipment and the process method for purifying high-purity EPA-ee are provided.
The first embodiment;
as shown in fig. 1, a separation apparatus for purifying high purity EPA-ee according to an embodiment of the present invention includes a stand 1, and the stand 1 is provided with a separation apparatus body 2, a plurality of chromatography columns 3, and a plurality of preparation bottles 4.
According to another aspect of the present invention, there is provided a process for purifying high purity EPA-ee separation equipment;
example two;
primary purification
Putting a fish oil raw material containing 70% of EPA-ee content into a preparation bottle to prepare a preparation solution, taking the preparation solution as a sample loading solution 1 to carry out continuous sample loading, separating by a Superchrom8000 series separation device and a chromatographic column, carrying out continuous separation, and removing EPA-ee post-impurities to obtain an intermediate product without post-impurities; after the sample solution 1 is purified into a product, concentrating the product into methanol-free water without diluting the product to be used as a sample solution 2; the high methanol flow rate is 1800mL/min, the 92% methanol-water (volume ratio) flow rate is 1710mL/min, and the sample loading flow rate is 6.75 mL/min. The density of the sample solution 1 is 1mg/mL, namely the concentration of EPA-ee in the sample solution 1 is 0.7 mg/mL; thus, 1 pure methanol with a high concentration of 1800mL per minute, an EPA-ee treatment of 4.725mg per minute, and a stationary phase of C18 at a column height of only 200 mm.
Secondary purification
Continuously loading the intermediate product serving as a loading liquid 2, and continuously separating by Superchrom7000 series separation equipment and a chromatographic column to remove EPA-ee precursor impurities to obtain a high-purity EPA-ee monomer;
in the secondary purification, the flow rate of 92% methanol-water (volume ratio) is 2070mL/min, the sample loading flow rate is 5.625mL/min, the dosage of 92% methanol-water (volume ratio) per minute is 2070mL, the EPA-ee amount processed per minute is 5.45625mg, the EPA-ee purity in the product is 99%, the stationary phase of the chromatographic column is C18, and the column height is only 200 mm.
Example three;
adopting a multi-column process mode:
comprises 6-12 pure chromatographic columns, 7-10 pure chromatographic columns and 8 pure chromatographic columns in detail; two pure chromatographic columns are 4-12, further 5-10 and further 6-7.
Adopting an asynchronous switching mode:
the mobile phase ratio is 90-100% methanol-water (volume ratio), further 90-95% methanol-water (volume ratio), further 92% methanol-water (volume ratio), one big switch is 15 min.
The temperature is 15-35 deg.C, further 20-30 deg.C, and further 25 deg.C.
The C18 filler has a particle size of 10-400 μm, further 15-100 μm, and further 20-40 μm.
The height of the packed column is 100-500mm, further 100-300mm and further 200 mm.
The sample solutions, i.e. the first pure sample solution 1 and the second pure sample solution 2, are diluted by 5 times and further diluted by 2 times without further dilution by 90-100 times of methanol water (volume ratio).
In summary, with the above technical solution of the present invention, the working principle and all the beneficial effects are as follows: the chromatographic process in the scheme only uses a methanol aqueous solvent, only one methanol proportion is used for purification, only one methanol proportion is used for regeneration, and the recovery and the application are simple; the reversed phase silica gel filler used by the separation equipment has good separation effect, simple GMP/FDA certification, reusability and small environmental pollution; the chromatographic column purification process has high filler utilization rate, large unit filler raw material treatment capacity per unit time, high productivity and small unit product methanol use amount; the chromatographic purification process is used for one-step purification, so that a 97% intermediate product can be obtained, and the intermediate product is purified in a two-step manner, so that an EPA product with the purity of more than 99% can be obtained; in a word, the super-chromatographic purification process has the advantages of low production cost, good product quality, high EPA yield and environmental friendliness, and is beneficial to industrial production.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. The separation equipment for purifying high-purity EPA-ee is characterized by comprising a placing seat (1), wherein a separation equipment body (2), a plurality of chromatographic columns (3) and a plurality of preparation bottles (4) are arranged on the placing seat (1).
2. A process for purifying high-purity EPA-ee separation equipment, which is used for the process for purifying the high-purity EPA-ee multi-column continuous separation equipment from the fish oil in claim 1, and comprises the following steps;
firstly, purifying the EPA content in the raw material to more than 70% by molecular distillation, and directly using fish oil with 70% of EPA-ee content as the raw material;
primary purification: putting a fish oil raw material containing 70% of EPA-ee content into a preparation bottle to prepare a preparation solution, taking the preparation solution as a sample loading solution 1 to carry out continuous sample loading, separating through a separation equipment body and a chromatographic column, continuously separating, and removing EPA-ee post-impurities to obtain an intermediate product without post-impurities;
after the sample solution 1 is purified into a product, concentrating the product into methanol-free water without diluting the product to be used as a sample solution 2;
and (3) secondary purification: continuously loading the sample by taking the intermediate product as a sample loading liquid 2, continuously separating by using a separation equipment body and a chromatographic column, and removing EPA-ee precursor impurities to obtain a high-purity EPA-ee monomer;
fish oil with 70% of EPA-ee content in the sample loading liquid 1 is not diluted;
the EPA-ee content of the sample liquid 2 is 97 percent, namely the EPA-ee concentration of a pure product concentrated solution is 0.97 mg/mL.
3. The process for purifying high-purity EPA-ee separation equipment according to claim 2, wherein the flow rate of high-methanol in one purification is 1800mL/min, the flow rate of 92% methanol-water (volume ratio) is 1710mL/min, and the sample loading flow rate is 6.75 mL/min. The density of the sample solution 1 is 1mg/mL, namely the concentration of EPA-ee in the sample solution 1 is 0.7 mg/mL; thus, 1 pure high methanol dosage of 1800mL per minute, EPA-ee dosage of 4.725mg per minute was processed.
4. The process of claim 3, wherein the flow rate of 92% methanol-water (vol.%) is 2070mL/min, the flow rate of sample is 5.625mL/min, the flow rate of 92% methanol-water (vol.%) is 2070mL/min, the EPA-ee amount processed per minute is 5.45625mg, and the EPA-ee purity in the product is 99%.
5. The process for purifying high purity EPA-ee separation equipment according to claim 4, wherein the stationary phase of the chromatographic column is C18, and the height of the column is only 200 mm.
6. The process for purifying high-purity EPA-ee separation equipment according to claim 5, wherein the mobile phase of the primary purification and the secondary purification is 92% ethanol water.
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Cited By (1)
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| CN115073292A (en) * | 2022-07-01 | 2022-09-20 | 江苏汉邦科技股份有限公司 | Preparation method of eicosapentaenoic acid ethyl ester |
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