阅读说明：本技术 供注射用聚山梨酯80及其制备方法 (Polysorbate 80 for injection and preparation method thereof ) 是由 张阳洋 李盛 曹金 黄虎 冉文华 肖舒文 朱智刚 李文文 刘淦 田佳 于 2019-09-27 设计创作，主要内容包括：本发明公开了一种供注射用聚山梨酯80及其制备方法。本发明聚山梨酯80的制备方法包括以下步骤：在催化剂存在下,将油酸山梨坦和聚乙二醇进行醚化反应,得到聚山梨酯80；所述的聚乙二醇为聚乙二醇300、聚乙二醇400和聚乙二醇600中的一种或多种；所述的聚乙二醇300与所述的油酸山梨坦的质量比为a,所述的聚乙二醇400与所述的油酸山梨坦的质量比为b,所述的聚乙二醇600与所述的油酸山梨坦的质量比为c,且0≤a≤2.93,0≤b≤2.20,0≤c≤1.47,a、b和c不同时为0。本发明的产品具有较低的过敏和溶血风险,安全性更高。<Image he="199" wi="700" file="DDA0002217751260000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses polysorbate 80 for injection and a preparation method thereof. The preparation method of polysorbate 80 comprises the following steps: in the presence of a catalyst, carrying out etherification reaction on sorbitan oleate and polyethylene glycol to obtain polysorbate 80; the polyethylene glycol is one or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600; the mass ratio of the polyethylene glycol 300 to the sorbitan oleate is a, the mass ratio of the polyethylene glycol 400 to the sorbitan oleate is b, the mass ratio of the polyethylene glycol 600 to the sorbitan oleate is c, a is more than or equal to 0 and less than or equal to 2.93, b is more than or equal to 0 and less than or equal to 2.20, c is more than or equal to 0 and less than or equal to 1.47, and a, b and c are not 0 at the same time. The product of the invention has lower risk of allergy and hemolysis and higher safety.)

1. A preparation method of polysorbate 80 is characterized by comprising the following steps: in the presence of a catalyst, carrying out etherification reaction on sorbitan oleate and polyethylene glycol to obtain polysorbate 80;

wherein the polyethylene glycol is one or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600;

the mass ratio of the polyethylene glycol 300 to the sorbitan oleate is a, the mass ratio of the polyethylene glycol 400 to the sorbitan oleate is b, the mass ratio of the polyethylene glycol 600 to the sorbitan oleate is c, a is more than or equal to 0 and less than or equal to 2.93, b is more than or equal to 0 and less than or equal to 2.20, c is more than or equal to 0 and less than or equal to 1.47, and a, b and c are not 0 at the same time;

2. the method for preparing polysorbate 80 according to claim 1, wherein in the etherification reaction, the polyethylene glycol is polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600 "polyethylene glycol 300 and polyethylene glycol 400", "polyethylene glycol 300 and polyethylene glycol 600", "polyethylene glycol 400 and polyethylene glycol 600", or "polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600";

and/or the catalyst is one or more of sulfuric acid, phosphoric acid, hydrofluoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, zinc chloride, ferric trichloride, aluminum chloride, boron trifluoride and boron trifluoride diethyl ether;

and/or in the etherification reaction, the mass ratio of the catalyst to the sorbitol is 0.001: 1-0.05: 1;

and/or, in the etherification reaction, a, b and c satisfy the following relations: 3a +4b +6c is 8.8;

and/or the etherification reaction is carried out in a high-pressure reaction kettle;

and/or the temperature of the etherification reaction is 70-135 ℃.

3. The method for preparing polysorbate 80 of claim 2, wherein when the polyethylene glycol is "polyethylene glycol 300 and polyethylene glycol 400", the a is 1.00, the b is 1.45;

and/or, when the polyethylene glycol is "polyethylene glycol 300 and polyethylene glycol 600", the a is 0.93, and the c is 1.00;

and/or, when the polyethylene glycol is "polyethylene glycol 400 and polyethylene glycol 600", the b is 1.00 and the c is 0.80;

and/or, when the polyethylene glycol is 'polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600', the 'a' is 0.10-2.30, the 'b' is 0.10-1.60, and the 'c' is 0.30-1.00;

and/or when the etherification reaction is carried out in a high-pressure reaction kettle, the vacuum degree of the high-pressure reaction kettle is more than or equal to 0.099 Mpa.

4. The method for producing polysorbate 80 of claim 3, wherein when the polyethylene glycol is "polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600", the "a" is 1.00, the "b" is 1.00, the "c" is 0.30 ", the" a "is 0.20, the" b "is 1.60, the" c "is 0.30", the "a" is 0.10, the "b" is 0.50, the "c" is 1.08 ", the" a "is 0.50, the" b "is 0.32, the" c "is 1.00", or the "a" is 2.33, the "b" is 0.30, and the "c" is 1.00 ".

5. The method for preparing polysorbate 80 according to claim 1 to 4, further comprising the steps of: in the presence of a catalyst, carrying out esterification reaction on sorbitol and oleic acid to obtain sorbitan oleate;

6. the method for preparing polysorbate 80 of claim 5, wherein in the esterification reaction, the catalyst is a base A and an acid A, the base A is one or more of an alkali metal base, an alkali metal carbonate and an alkali metal bicarbonate, and the acid A is phosphoric acid and/or phosphorous acid;

and/or in the esterification reaction, the sorbitol is sorbitol powder and/or 70% sorbitol aqueous solution;

and/or, in the esterification reaction, the oleic acid is high-purity oleic acid with the content of more than 98 percent;

and/or in the esterification reaction, the mass ratio of the oleic acid to the sorbitol is 1.0-2.5;

and/or the esterification reaction is carried out under the vacuum degree of more than 0.09 MPa;

and/or the temperature of the esterification reaction refers to the temperature in the stage heating process and the heat preservation reaction process, the stage heating process is 80-180 ℃, and the heat preservation process is 195-205 ℃.

7. The method for preparing polysorbate 80 according to claim 6, wherein the mass ratio of the base A to the sorbitol in the esterification reaction is 0.002:1 to 0.01: 1;

and/or in the esterification reaction, the mass ratio of the acid A to the sorbitol is 0.002: 1-0.01: 1;

and/or, the alkali A is added in the form of aqueous solution; when the base A is added in the form of an aqueous solution; the concentration of the alkali A is 10-40%, and the concentration is the mass percentage of the mass of the alkali A to the total mass of the solution;

and/or, the acid A is added in the form of aqueous solution; when the acid A is added in the form of an aqueous solution; the concentration of the acid A is 10-40%, and the concentration is the mass percentage of the mass of the acid A to the total mass of the solution.

8. A polysorbate 80, wherein the polysorbate 80 is prepared according to the preparation method of the polysorbate 80 as claimed in any one of claims 1 to 7.

9. Polysorbate 80 according to claim 8, characterized in that it has the following characteristics: color: colorless; acid value: 0.1 to 0.2; ③ saponification value: 40 to 51; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.4-99.6%, wherein the oleic acid content is the mass percentage of the oleic acid in the total mass of all fatty acids.

10. The polysorbate 80 of claim 9, wherein the polysorbate 80 is any one of polysorbate 80 having: "color: colorless; acid value: 0.1; ③ saponification value: 46; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.5 percent, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 50; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.7 percent of oleic acid, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 47; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.4 percent of the total mass of all fatty acids, wherein the oleic acid content is the mass percent of the oleic acid,

"color: colorless; acid value: 0.1; ③ saponification value: 44; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.2 percent of the total mass of all fatty acids, wherein the oleic acid content is the mass percent of the oleic acid,

"color: colorless; acid value: 0.2; ③ saponification value: 48; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.1 percent of oleic acid, wherein the content of the oleic acid is that the mass of the oleic acid accounts for the total mass of all fatty acids

"color: colorless; acid value: 0.1; ③ saponification value: 51; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.0 percent, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.1; ③ saponification value: 49; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.4 percent of oleic acid, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 45, a first step of; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.6 percent, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 48; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.6 percent of the total mass of all fatty acids, wherein the oleic acid content is the mass percent of the oleic acid,

"color: colorless; acid value: 0.2; ③ saponification value: 45, a first step of; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.7 percent of oleic acid, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

And, "color: colorless; acid value: 0.1; ③ saponification value: 51; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.2 percent, wherein the content of the oleic acid is the mass percent of the mass of the oleic acid in the total mass of all fatty acids ".

Technical Field

The invention relates to a polyester 80 for injection and a preparation method thereof.

Background

Polysorbate 80, also known as tween 80, is used as a dispersant and solubilizer for low water-soluble drugs in the pharmaceutical industry, wherein high-purity polysorbate 80 can be used as a solubilizer for injection preparations. In the traditional Chinese medicine injection, polysorbate 80 is used as a solubilizer, and in the biological preparations which are developed rapidly in recent years, polysorbate 80 is an excellent protein protective agent. As an adjuvant with a relatively high frequency of use in injections, the safety of polysorbate 80 is very important. Therefore, the product polysorbate 80 for injection is collected from the 'Chinese pharmacopoeia' 2015 edition, and the quality standard of the product is improved from the aspects of oleic acid content, impurities, color, saponification value, peroxide value and the like.

There are generally two synthetic methods for polysorbate 80: one is that sorbitol is dehydrated, esterified with oleic acid and then polymerized with ethylene oxide to obtain (ester first and ether later); the other is prepared by polymerizing ethylene oxide after dehydration of sorbitol and esterifying with fatty acid (first ether and then ester). However, ethylene oxide is used in both of the above two synthetic methods, and is a toxic carcinogen, a flammable and explosive gas; and the final product obtained contains ethylene glycol, diethylene glycol, triethylene glycol, dioxane, and high molecular weight substances. The publications CN102585198B, CN1012351139A, CN101983977B, US8334397 and the like all disclose methods for synthesizing polysorbate 80 by using ethylene oxide as a reaction raw material, but the final products all contain the above impurities, and cannot easily reach the injection level standard in the chinese pharmacopoeia without being refined. At present, adverse reactions (such as anaphylactic reaction and hemolytic reaction) in clinical use of the traditional Chinese medicine injection are mostly related to polysorbate 80. Therefore, providing a safer and more effective method for synthesizing polysorbate 80 for injection has become a very urgent research subject.

Therefore, there is a need in the art to develop a more safe polysorbate 80 for injection.

Disclosure of Invention

The invention aims to overcome the defect of adverse reactions (such as anaphylactic reaction and hemolytic reaction) of polysorbate 80 for injection in clinical use in the prior art, and provides polysorbate 80 for injection and a preparation method thereof. The product of the invention does not contain impurities such as ethylene glycol, diethylene glycol, triethylene glycol, dioxane, high molecular weight substances and the like, has lower allergy and hemolysis risks, has higher safety, and meets the quality requirements of 2015 edition Chinese pharmacopoeia.

The present invention solves the above-mentioned problems by the following means.

The invention provides a preparation method of polysorbate 80, which comprises the following steps: in the presence of a catalyst, carrying out etherification reaction on sorbitan oleate and polyethylene glycol to obtain polysorbate 80;

wherein the polyethylene glycol is one or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600;

the mass ratio of the polyethylene glycol 300 to the sorbitan oleate is a, the mass ratio of the polyethylene glycol 400 to the sorbitan oleate is b, the mass ratio of the polyethylene glycol 600 to the sorbitan oleate is c, a is more than or equal to 0 and less than or equal to 2.93, b is more than or equal to 0 and less than or equal to 2.20, c is more than or equal to 0 and less than or equal to 1.47, and a, b and c are not 0 at the same time;

in the etherification reaction, the polyethylene glycol may be polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, "polyethylene glycol 300 and polyethylene glycol 400", "polyethylene glycol 300 and polyethylene glycol 600", "polyethylene glycol 400 and polyethylene glycol 600", or "polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600".

Wherein, when the polyethylene glycol is polyethylene glycol 300 and polyethylene glycol 400, the a is 1.00 and the b is 1.45.

Wherein, when the polyethylene glycol is polyethylene glycol 300 and polyethylene glycol 600, the a is 0.93, and the c is 1.00.

Wherein, when the polyethylene glycol is polyethylene glycol 400 and polyethylene glycol 600, the b is 1.00 and the c is 0.80.

Wherein, when the polyethylene glycol is polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600, the a can be 0.10-2.30, the b can be 0.10-1.60, and the c can be 0.30-1.00 "; further, the phrase "a is 1.00, b is 1.00, c is 0.30", "a is 0.20, b is 1.60, c is 0.30", "a is 0.10, b is 0.50, c is 1.08", "a is 0.50, b is 0.32, c is 1.00", or "a is 2.33, b is 0.30, c is 1.00".

In the etherification reaction, the catalyst can be one or more of sulfuric acid, phosphoric acid, hydrofluoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, zinc chloride, ferric trichloride, aluminum chloride, boron trifluoride and boron trifluoride diethyl ether.

In the etherification reaction, the mass ratio of the catalyst to the sorbitol can be 0.001: 1-0.05: 1, e.g. 0.042: 1. 0.03: 1. 0.002: 1. 0.02: 1. 0.004: 1. 0.035: 1. 0.008: 1. 0.025: 1. 0.014: 1.

in the etherification reaction, a, b and c satisfy the following relations: 3a +4b +6c is 8.8.

The etherification reaction can also be carried out in a high-pressure reaction kettle. The vacuum degree of the high-pressure reaction kettle is more than or equal to 0.099 Mpa.

The temperature of the etherification reaction may be 70 to 135 ℃, for example 115 ℃, 125 ℃, 80 ℃, 90 ℃, 70 ℃, 120 ℃, 115 ℃, 95 ℃, 105 ℃ and 100 ℃.

The etherification reaction time can be 2-10 h, such as 3.5h, 6.5h, 8.0h, 5.0h, 2.0h, 6.0h, 4.0h, 7.0h and 9.0 h.

After the etherification reaction is finished, the etherification reaction can also comprise filtration. The filtration may be plate and frame filtration. The filtration medium is a filter membrane, for example a 0.22um filter membrane.

The preparation method of polysorbate 80 can further comprise the following steps: in the presence of a catalyst, carrying out esterification reaction on sorbitol and oleic acid to obtain sorbitan oleate;

the operations and conditions of the esterification reaction may be those conventional in the art, and the following are preferred in the present invention:

in the esterification reaction, the catalyst can be a base a and an acid a, the base a can be one or more of an alkali metal base (such as potassium hydroxide and sodium hydroxide), an alkali metal carbonate (such as sodium carbonate) and an alkali metal bicarbonate (such as sodium bicarbonate), and the acid a can be phosphoric acid and/or phosphorous acid.

Wherein, the alkali A is preferably added in the form of aqueous solution. When the alkali A is added in the form of an aqueous solution, the concentration of the alkali A can be 10-40%, and the concentration is the mass percentage of the mass of the alkali A to the total mass of the solution, such as 20% and 30%.

Wherein, the acid A is preferably added in the form of an aqueous solution. When the acid a is added in the form of an aqueous solution, the concentration of the acid a may be 10 to 40% by mass as a percentage of the mass of the acid a to the total mass of the solution, for example 20%, 30%.

In the esterification reaction, the mass ratio of the alkali A to the sorbitol can be 0.002: 1-0.01: 1, for example 0.005:1, 0.007: 1.

In the esterification reaction, the mass ratio of the acid A to the sorbitol may be 0.002:1 to 0.01:1, for example, 0.003:1 or 0.005: 1.

In the esterification reaction, the sorbitol can be sorbitol powder and/or 70% sorbitol aqueous solution. The content of reducing sugar in the sorbitol can be less than 0.05 percent, and the total sugar content can be more than 0.3 percent.

In the esterification reaction, the oleic acid can be high-purity oleic acid with the content of more than 98 percent.

In the esterification reaction, the mass ratio of the oleic acid to the sorbitol can be 1.0-2.5, such as 1.5 and 2.0.

The esterification reaction can be carried out under the vacuum degree of more than 0.09 MPa.

The temperature of the esterification reaction refers to the temperature in the stage heating process and the heat preservation reaction process, the stage heating process can be 80-180 ℃, and the heat preservation process can be 195-205 ℃.

The time of the esterification reaction refers to the time in the stage heating process and the heat preservation reaction process, the time of the stage heating process can be more than or equal to 2 hours, and the time of the heat preservation process can be more than or equal to 6 hours.

The invention also provides a preparation method of the polysorbate 80, and the polysorbate 80 is prepared by the preparation method of the polysorbate 80.

The polysorbate 80 preferably has the following characteristics: color: colorless; acid value: 0.1 to 0.2; ③ saponification value: 40 to 51; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.4-99.6%, wherein the oleic acid content is the mass percentage of the oleic acid in the total mass of all fatty acids.

The polysorbate 80 is preferably any polysorbate 80 with the following characteristics: "color: colorless; acid value: 0.1; ③ saponification value: 46; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.5 percent, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 50; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.7 percent of oleic acid, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 47; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.4 percent of the total mass of all fatty acids, wherein the oleic acid content is the mass percent of the oleic acid,

"color: colorless; acid value: 0.1; ③ saponification value: 44; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.2 percent of the total mass of all fatty acids, wherein the oleic acid content is the mass percent of the oleic acid,

"color: colorless; acid value: 0.2; ③ saponification value: 48; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.1 percent of oleic acid, wherein the content of the oleic acid is that the mass of the oleic acid accounts for the total mass of all fatty acids

"color: colorless; acid value: 0.1; ③ saponification value: 51; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.0 percent, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.1; ③ saponification value: 49; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.4 percent of oleic acid, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 45, a first step of; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.6 percent, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.2; ③ saponification value: 48; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.6 percent of the total mass of all fatty acids, wherein the oleic acid content is the mass percent of the oleic acid,

"color: colorless; acid value: 0.2; ③ saponification value: 45, a first step of; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 98.7 percent of oleic acid, wherein the content of the oleic acid is the mass percentage of the oleic acid in the total mass of all fatty acids

"color: colorless; acid value: 0.1; ③ saponification value: 51; peroxide value: 0.1; ethylene oxide is not detected; sixthly, the dioxane is not detected; no glycol is detected; eighty percent of diethylene glycol is not detected; ninthly, not detecting triethylene glycol; content of oleic acid in r: 99.2 percent, wherein the content of the oleic acid is the mass percent of the mass of the oleic acid in the total mass of all fatty acids ".

In the polysorbate 80, the chromaticity detection method can be performed by adopting a colorimeter, and a platinum-cobalt chromaticity standard solution is selected for calibration, which is determined by referring to the general rule (0901) of the Chinese pharmacopoeia 2015 edition.

In the polysorbate 80, the acid value, the saponification value and the peroxide value can be measured by referring to the general rule (0713) of the Chinese pharmacopoeia 2015 edition.

In the polysorbate 80, the ethylene oxide and the dioxane can be detected by gas chromatography, which refers to the method of "ethylene oxide and dioxane" in the fourth polysorbate 80 (for injection) of the pharmacopoeia 2015 edition of China. The lower limit of detection by gas chromatography was 0.1 ppm.

In the polysorbate 80, the ethylene glycol, the diethylene glycol and the triethylene glycol can be detected by gas chromatography, which refers to the method of "ethylene glycol, diethylene glycol and triethylene glycol" in polysorbate 80 (for injection) of the fourth part of the pharmacopoeia 2015 edition. The lower limit of detection by gas chromatography was 0.1 ppm.

In the polysorbate 80, the oleic acid content can be detected by gas chromatography, which refers to the method of "fatty acid composition" of polysorbate 80 (for injection) in the fourth part of the pharmacopoeia 2015 edition.

In the polysorbate 80, the impurity having a molecular weight of 2000 or more can be measured by electrospray mass spectrometry (ESI-MS). The instrument for the determination may be an AB SCIEX 4500 mass spectrometer. The conditions for the assay may be: the air curtain air setting is 40 psi; the ion source voltage is set to-4500V in the negative ion mode; the turbine heater is set to 500 ℃; atomizing gas setting is 55 psi; the heater was set at 40 psi; the prepared sample is 1mg/L of polysorbate 80 methanol solution.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the impurities of ethylene glycol, diethylene glycol, triethylene glycol and dioxane in the polysorbate 80 are not detected, macromolecular impurities with molecular weight over 2000 are avoided, the risk of allergy and hemolysis is low, and the safety is higher.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.