Method for reducing content of isomers in ethyl polyenoate and application of method

Abstract

The invention belongs to the technical field of purification of ethyl polyenoate, and particularly relates to a method for reducing the content of isomers in ethyl polyenoate and application thereof, the method comprises the following steps: placing ethyl polyenoate in molecular rectification equipment for first molecular rectification, and removing low-boiling-point substances and part of low-boiling-point saturated fatty acid; and placing the rectified heavy phase obtained by the first molecular rectification in molecular rectification equipment for second molecular rectification to remove isomers. According to the method for reducing the content of the isomers in the ethyl polyenoate, the principle of physical purification is adopted, the isomers in the ethyl polyenoate can be effectively removed through two times of molecular rectification, and the content of the isomers in the ethyl polyenoate is reduced to 0.2% or below, so that the purity and the quality of the product are improved. In addition, the method is high in yield, low in energy consumption, simple to operate, capable of utilizing conventional treatment devices of chemical plants, low in economic cost and suitable for industrial continuous production, and has important significance on preparation of high-quality ethyl polyenoate drugs.

Description

Technical Field

[0001] The invention relates to the technical field of polyenoic acid ethyl ester purification, in particular to a method for reducing the isomer content in polyenoic acid ethyl ester and application thereof. Background Art

[0002] Ethyl polyenoate, as an important lipid-lowering drug, is mainly composed of eicosapentaenoic acid ethyl ester (EPA-E) and docosahexaenoic acid ethyl ester (DHA-E), and these two components have significant lipid-lowering, vasodilating and anti-thrombotic effects. However, in the production process of ethyl polyenoate, a certain amount of isomers are often produced, and the presence of these isomers not only affects the purity of the product, but also may have a negative impact on the efficacy and safety of the drug. Therefore, developing an effective isomer removal method is of great significance for improving the quality and efficacy of ethyl polyenoate.

[0003] The production of polyoleic acid ethyl esters usually uses fish oil ethyl ester as raw material, increases the content of active ingredients through urea adsorption, and then uses multi-stage molecular distillation or vacuum distillation to increase the content of EPA-E and DHA-E to a high content, and then decolorizes, deodorizes and sterilizes it. However, in this series of production processes, due to the complexity of raw materials, improper control of reaction conditions and limitations of separation technology, a certain amount of isomers are often produced.

[0004] At present, there are mainly the following methods for removing isomers from polyenoic acid ethyl esters:

[0005] Recrystallization method: By selecting appropriate solvents and crystallization conditions, the solubility of isomers in the solvent is reduced, thereby achieving separation of isomers. However, the recrystallization method often has the disadvantages of low yield, complex operation and difficulty in completely removing isomers.

[0006] Chemical treatment: Use chemical reactions to convert isomers into easily separable substances, which are then removed by extraction, distillation, etc. However, chemical treatment may introduce new impurities, and the reaction conditions are difficult to control, posing a potential threat to product quality and safety.

[0007] Chromatographic separation: The mixture is separated using a chromatographic column, and the separation is achieved based on the differences in the adsorption and elution properties of the isomers on the chromatographic column. However, chromatographic separation has the disadvantages of high equipment cost, complex operation and limited processing capacity.

[0008] In view of the limitations of existing isomer removal methods, developing an efficient, low-cost and easy-to-operate method to reduce the isomer content in polyenoic acid ethyl esters is of great significance for improving the quality and efficacy of polyenoic acid ethyl esters. Summary of the invention

[0009] The object of the present invention is to provide a method for reducing the isomer content in ethyl polyenoate, which can effectively remove the isomers in ethyl polyenoate and make the isomer content in ethyl polyenoate reach below 0.2%.

[0010] In a first aspect, the present invention provides a method for reducing the isomer content in ethyl polyenoate, comprising the following steps:

[0011] The polyenoic acid ethyl ester is placed in a molecular distillation device for a first molecular distillation to remove low-boiling substances and part of low-boiling point saturated fatty acids;

[0012] The distillation heavy phase obtained from the first molecular distillation is placed in a molecular distillation device for a second molecular distillation to remove isomers.

[0013] The method for reducing the isomer content in ethyl polyenoate adopts the principle of physical purification. Firstly, the ethyl polyenoate is placed in a molecular distillation device for a first molecular distillation to remove low-boiling substances such as myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and some low-boiling saturated fatty acids. Then, the heavy phase obtained by the first molecular distillation is placed in the molecular distillation device for a second molecular distillation to further remove EPA isomers and DHA isomers in the ethyl polyenoate. The light phase of the second molecular distillation is collected, and the isomer content of the ethyl polyenoate can be reduced to less than 0.2%, thereby improving the purity and quality of the product.

[0014] As a preferred embodiment of the present technical solution, during the first molecular distillation, the feed rate is controlled to be 300-400 kg / h, the low-boiling-point material discharge rate is 100-270 kg / h, and the high-boiling-point material discharge rate is 200-270 kg / h.

[0015] Among them, controlling the feed rate within the range of 300-400kg / h can ensure that the material processing capacity in the molecular distillation equipment is moderate, neither overloaded nor too sparse, which is conducive to the separation and removal of impurities. The discharge rate of low-boiling substances is controlled at 100-270kg / h, and the discharge rate of high-boiling substances is controlled at 200-270kg / h, which helps to discharge the separated low-boiling substances and high-boiling substances from the equipment in time to avoid their interference with the subsequent separation process.

[0016] As a preferred embodiment of the present technical solution, during the first molecular distillation, the heating temperature is controlled to be 200-220°C and the reflux temperature is 100-130°C. The heating temperature is controlled within the range of 200-220°C to ensure that the material has sufficient energy for vaporization and separation during the molecular distillation process, while avoiding thermal deterioration of the material due to excessively high temperature; and the reflux temperature is controlled within the range of 100-130°C, which helps to reflux some of the incompletely separated materials into the tower for further separation and purification.

[0017] As a preferred embodiment of the present technical solution, during the first molecular distillation, the top pressure is controlled to be 0.5-50 mbar and the top temperature is controlled to be 140-160°C. The top pressure is controlled within the range of 0.5-50 mbar and the top temperature is controlled within the range of 140-160°C. These two parameters jointly determine the vacuum degree and temperature distribution in the tower, thereby affecting the vaporization and separation effect of the material. Appropriate top pressure and top temperature help optimize the separation process and improve the purity of the product.

[0018] As a preferred embodiment of the present technical solution, during the first molecular distillation, the reflux ratio is controlled to be 0.5-5 and the tower pressure difference is 0.5-50mbar. The reflux ratio refers to the ratio of the amount of refluxed material to the amount of produced material. An appropriate reflux ratio can ensure that there is enough material in the tower for circulation and separation, thereby improving separation efficiency and product purity; and the tower pressure difference is controlled within the range of 0.5-50mbar, which helps to maintain a stable flow state in the tower and avoid material retention or blockage in the tower, thereby affecting the separation effect.

[0019] As a preferred embodiment of the present technical solution, during the second molecular distillation, the feed rate is controlled to be 150-250 kg / h, the low boiling point material discharge rate is 90-150 kg / h, and the high boiling point material discharge rate is 60-100 kg / h.

[0020] Specifically, during the second molecular distillation, the heating temperature is controlled to be 200-220°C and the reflux temperature is controlled to be 100-130°C.

[0021] Specifically, during the second molecular distillation, the top pressure is controlled to be 0.5-50 mbar and the top temperature is controlled to be 150-170°C.

[0022] Specifically, during the second molecular distillation, the reflux ratio is controlled to be 0.5-5 and the tower pressure difference is controlled to be 0.5-50 mbar.

[0023] In a second aspect, the present invention further provides a polyenoic acid ethyl ester product prepared by the above method for reducing the isomer content in polyenoic acid ethyl ester, wherein the isomer content in the polyenoic acid ethyl ester product is below 0.2%.

[0024] The method for reducing the isomer content in ethyl polyenoate of the present invention specifically comprises the following steps:

[0025] (1) Under vacuum / negative pressure conditions, the polyenoic acid ethyl ester raw material is pumped into a molecular distillation device through a feed pump for the first molecular distillation;

[0026] (2) In the above step (1), the feed rate is controlled to be 300-400 kg / h; the discharge rate of low-boiling substances is 100-270 kg / h, and the discharge rate of high-boiling substances is 200-270 kg / h;

[0027] (3) During the first molecular distillation in step (1), the heating temperature is controlled to be 200-220°C and the reflux temperature is controlled to be 100-130°C;

[0028] (4) During the first molecular distillation in step (1), the top pressure is controlled to be 0.5-50 mbar and the top temperature is controlled to be 140-160° C.;

[0029] (5) During the first molecular distillation in step (1), the reflux ratio is 0.5-5, preferably 1.5-3.5, and the tower pressure difference is 0.5-50 mbar;

[0030] (6) according to the above steps, the low-boiling substances and part of the low-boiling saturated fatty acids in the polyenoic acid ethyl ester are removed, and the heavy phase of the first molecular distillation is collected;

[0031] (7) The heavy phase of the first molecular distillation in step (6) is pumped into a molecular distillation device through a feed pump for a second molecular distillation;

[0032] (8) In the above step (7), the feed rate is controlled to be 150-250 kg / h, the discharge rate of low boiling substances is controlled to be 90-150 kg / h, and the discharge rate of high boiling substances is controlled to be 60-100 kg / h.

[0033] (9) During the second molecular distillation in step (7), the heating temperature is controlled to be 200-220°C and the reflux temperature is controlled to be 100-130°C;

[0034] (10) During the second molecular distillation in step (7), the top pressure is controlled to be 0.5-50 mbar and the top temperature is controlled to be 150-170° C.;

[0035] (11) During the second molecular distillation in step (7), the reflux ratio is controlled to be 0.5-5 and the tower pressure difference is controlled to be 0.5-50 mbar;

[0036] (12) According to the above steps, the isomers in the ethyl polyenoate are removed, and the light phase of the second molecular distillation is collected, which is the ethyl polyenoate.

[0037] The method for reducing the isomer content in ethyl polyenoate of the present invention has at least the following beneficial effects:

[0038] The method for reducing the isomer content in ethyl polyenoate adopts the principle of physical purification, firstly, ethyl polyenoate is placed in a molecular distillation device for a first molecular distillation, and low-boiling substances such as myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and some low-boiling saturated fatty acids are removed, and then the heavy phase obtained by the first molecular distillation is placed in the molecular distillation device for a second molecular distillation, so as to further remove the EPA isomer and the DHA isomer in the ethyl polyenoate, and the light phase of the second molecular distillation is collected, so that the isomer content of the ethyl polyenoate can be reduced to less than 0.2%, thereby improving the purity and quality of the product. In addition, the method has high yield, low energy consumption, simple operation, can utilize conventional processing equipment of chemical plants, has low economic cost, is suitable for industrial continuous production, and is of great significance for preparing high-quality ethyl polyenoate drugs. DETAILED DESCRIPTION

[0039] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0040] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form also includes the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this description, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0041] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] Example 1

[0043] The present embodiment provides a method for reducing the isomer content in ethyl polyenoate, comprising the following steps:

[0044] The molecular distillation equipment was evacuated to a top pressure of 1 mbar, and the polyolefin ethyl ester raw material was pumped into the molecular distillation equipment through a feed pump, and the feed pump speed was controlled at 300-400 kg / h;

[0045] The heating temperature of the molecular distillation equipment is controlled to be 200° C., the reflux ratio is controlled to be 3.0 for the first molecular distillation, and the reflux temperature is controlled to be 100-130° C., the tower top temperature is controlled to be 140-160° C., and the tower pressure difference is controlled to be 0.5-50 mbar. Low boiling substances and part of low boiling point saturated fatty acids in ethyl polyenoate are removed by the first molecular distillation, the discharge rate of the low boiling substances is 100-270 kg / h, the heavy phase of the first molecular distillation is collected, and the discharge rate of high boiling substances is 200-270 kg / h.

[0046] The molecular distillation equipment is evacuated to a top pressure of 1 mbar, and the heavy phase material of the first molecular distillation is pumped into the molecular distillation equipment through a feed pump for a second molecular distillation, and the feed pump speed is controlled at 150-250 kg / h;

[0047] The heating temperature of the molecular distillation equipment is controlled to be 200° C., the reflux ratio is controlled to be 3.0 for the second molecular distillation, and the reflux temperature is controlled to be 100-130° C., the tower top temperature is controlled to be 150-170° C., and the tower pressure difference is controlled to be 0.5-50 mbar. The isomers in the ethyl polyenoate are removed by the second molecular distillation, the discharge rate of the high boiling products is 60-100 kg / h, the light phase of the second molecular distillation is collected, and the discharge rate of the low boiling products is 90-150 kg / h.

[0048] The test showed that the isomer content in the ethyl polyenoate treated in this example was 0.15%.

[0049] Example 2

[0050] The present embodiment provides a method for reducing the isomer content in ethyl polyenoate, comprising the following steps:

[0051] The molecular distillation equipment was evacuated to a top pressure of 1 mbar, and the polyolefin ethyl ester raw material was pumped into the molecular distillation equipment through a feed pump, and the feed pump speed was controlled at 300-400 kg / h;

[0052] The heating temperature of the molecular distillation equipment is controlled to be 220° C., and the reflux ratio is 3.0 for the first molecular distillation. At the same time, the reflux temperature is controlled to be 100-130° C., the tower top temperature is 140-160° C., and the tower pressure difference is 0.5-50 mbar. Low boiling substances and part of low-boiling saturated fatty acids in ethyl polyenoate are removed by the first molecular distillation. The discharge rate of the low boiling substances is 100-270 kg / h. The heavy phase of the first molecular distillation is collected, and the discharge rate of high boiling substances is 200-270 kg / h.

[0053] The molecular distillation equipment is evacuated to a top pressure of 1 mbar, and the heavy phase material of the first molecular distillation is pumped into the molecular distillation equipment through a feed pump for a second molecular distillation, and the feed pump speed is controlled at 150-250 kg / h;

[0054] The heating temperature of the molecular distillation equipment is controlled at 220°C, the reflux ratio is controlled at 3.0, and the second molecular distillation is performed. At the same time, the reflux temperature is controlled at 100-130°C, the tower top temperature is controlled at 150-170°C, and the tower pressure difference is controlled at 0.5-50 mbar. The isomers in the ethyl polyenoate are removed by the second molecular distillation, the high boiling point discharge rate is 60-100 kg / h, the light phase of the second molecular distillation is collected, and the low boiling point discharge rate is 90-150 kg / h.

[0055] The test showed that the isomer content in the ethyl polyenoate treated in this example was 0.1%.

[0056] Example 3

[0057] The present embodiment provides a method for reducing the isomer content in ethyl polyenoate, comprising the following steps:

[0058] The molecular distillation equipment was evacuated to a top pressure of 10 mbar, and the polyenoic acid ethyl ester raw material was pumped into the molecular distillation equipment through a feed pump, and the feed pump speed was controlled at 300-400 kg / h;

[0059] The heating temperature of the molecular distillation equipment is controlled to be 210° C., the reflux ratio is controlled to be 0.5-5 for the first molecular distillation, and the reflux temperature is controlled to be 100-130° C., the tower top temperature is controlled to be 140-160° C., and the tower pressure difference is controlled to be 0.5-50 mbar. Low boiling substances and part of low boiling point saturated fatty acids in ethyl polyenoate are removed by the first molecular distillation, the discharge rate of the low boiling substances is 100-270 kg / h, the heavy phase of the first molecular distillation is collected, and the discharge rate of high boiling substances is 200-270 kg / h.

[0060] The molecular distillation equipment is evacuated to a top pressure of 1 mbar, and the heavy phase material of the first molecular distillation is pumped into the molecular distillation equipment through a feed pump for a second molecular distillation, and the feed pump speed is controlled at 150-250 kg / h;

[0061] The heating temperature of the molecular distillation equipment is controlled to be 210° C., and the reflux ratio is controlled to be 0.5-5 for the second molecular distillation. Meanwhile, the reflux temperature is controlled to be 100-130° C., the tower top temperature is controlled to be 150-170° C., and the tower pressure difference is controlled to be 0.5-50 mbar. The isomers in the ethyl polyenoate are removed by the second molecular distillation, the high-boiling-substance discharge rate is 60-100 kg / h, the light phase of the second molecular distillation is collected, and the low-boiling-substance discharge rate is 90-150 kg / h.

[0062] The test showed that the isomer content in the ethyl polyenoate treated in this example was 0.13%.

[0063] Comparative Example 1

[0064] This comparative example is basically the same as Example 1, except that during the first molecular distillation and the second molecular distillation, the molecular distillation equipment was evacuated to a top pressure of 100 mbar.

[0065] After testing, the isomer content of the ethyl polyenoate treated in this control example was 2.7%.

[0066] Comparative Example 2

[0067] This comparative example is basically the same as Example 1, except that: during the first molecular distillation, the heating temperature of the molecular distillation equipment is adjusted to 230°C.

[0068] After testing, the isomer content of the ethyl polyenoate treated in this control example was 3.5%.

[0069] Comparative Example 3

[0070] This comparative example is basically the same as Example 1, except that during the second molecular distillation, the reflux ratio of the molecular distillation equipment is adjusted to 6.

[0071] After testing, the isomer content of the ethyl polyenoate treated in this control example was 4.7%.

[0072] In summary, the method for reducing the isomer content in ethyl polyenoate of the present invention adopts the principle of physical purification, firstly, ethyl polyenoate is placed in a molecular distillation device for the first molecular distillation, and low-boiling substances and part of low-boiling saturated fatty acids such as myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid are removed, and then the heavy phase obtained by the first molecular distillation is placed in a molecular distillation device for the second molecular distillation, so as to further remove the EPA isomer and the DHA isomer in the ethyl polyenoate, and the light phase of the second molecular distillation is collected, so that the isomer content of ethyl polyenoate can be reduced to less than 0.2%, thereby improving the purity and quality of the product. In addition, the method has high yield, low energy consumption, simple operation, and can utilize conventional processing equipment of chemical plants, low economic cost, and is suitable for industrial continuous production, which is of great significance for preparing high-quality ethyl polyenoate drugs.

[0073] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for reducing the isomer content in ethyl polyenoate, characterized in that: The following steps are involved: The polyenoic acid ethyl ester is placed in a molecular distillation device for a first molecular distillation to remove low-boiling substances and part of low-boiling point saturated fatty acids; The distillation heavy phase obtained from the first molecular distillation is placed in a molecular distillation device for a second molecular distillation to remove isomers.

2. The method for reducing isomer content in ethyl polyenoate according to claim 1, characterized in that: During the first molecular distillation, the feed rate is controlled to be 300-400 kg / h, the low-boiling-point material discharge rate is 100-270 kg / h, and the high-boiling-point material discharge rate is 200-270 kg / h.

3. The method for reducing isomer content in ethyl polyenoate according to claim 1, characterized in that, During the first molecular distillation, the heating temperature is controlled to be 200-220°C and the reflux temperature is controlled to be 100-130°C.

4. The method for reducing isomer content in ethyl polyenoate according to claim 1, characterized in that, During the first molecular distillation, the top pressure is controlled to be 0.5-50 mbar and the top temperature is controlled to be 140-160°C.

5. The method for reducing the isomer content in ethyl polyenoate according to claim 1, characterized in that, During the first molecular distillation, the reflux ratio is controlled to be 0.5-5 and the tower pressure difference is 0.5-50 mbar.

6. The method for reducing the isomer content in ethyl polyenoate according to claim 1, characterized in that: During the second molecular distillation, the feed rate is controlled to be 150-250 kg / h, the low-boiling-point material discharge rate is 90-150 kg / h, and the high-boiling-point material discharge rate is 60-100 kg / h.

7. The method for reducing the isomer content in ethyl polyenoate according to claim 1, characterized in that: During the second molecular distillation, the heating temperature is controlled to be 200-220°C and the reflux temperature is controlled to be 100-130°C.

8. The method for reducing the isomer content in ethyl polyenoate according to claim 1, characterized in that: During the second molecular distillation, the top pressure is controlled to be 0.5-50 mbar and the top temperature is controlled to be 150-170°C.

9. The method for reducing the isomer content in ethyl polyenoate according to claim 1, characterized in that, During the second molecular distillation, the reflux ratio is controlled to be 0.5-5 and the tower pressure difference is 0.5-50 mbar.

10. A polyolefin ethyl ester product, characterized in that: The polyenoic acid ethyl ester is prepared by the method for reducing the isomer content in the polyenoic acid ethyl ester according to any one of claims 1 to 9, wherein the isomer content in the polyenoic acid ethyl ester product is below 0.2%.