Method for recovering diene from diene alcohol ketone acetate mother liquor

Abstract

The invention provides a method for recovering diene from a diene alcohol ketone acetate mother solution. The method comprises the following steps: S1, filtering and intercepting macromolecular impurities by using a ceramic membrane; S2, adding a composite acidifying agent for gradient acidification until the pH value is 2.0 + / -0.1; and S3, extracting by using an ultrasonic-assisted isopropyl acetate-cyclohexane mixed solvent. S4, performing reverse washing with a washing solution, and performing vacuum concentration; s5, dropwise adding solvents such as cyclohexane into the crude product in a programmed manner, and performing temperature-controlled crystallization in three stages, and S6, performing supercritical CO2 fluid washing and drying, according to the method, through the synergistic effect of compound acidification, ultrasonic extraction, programmed crystallization, supercritical washing and the like, efficient recovery of diene is realized, the purity of a finished product is greater than or equal to 99.5%, and the method has the advantages of thorough impurity removal, high yield, greenness, environmental protection and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemicals, and in particular to a method for recovering diene from diene ketone acetate mother liquor. Background Art

[0002] Diene ketone acetate (abbreviated as "diene"), chemical name: 5.16-pregnadiene-3β-ol-20-ketone-acetate, molecular formula: C 23 H 32 O3, with a molecular weight of 356.5, has the nucleus of the steroid hormone cyclopentane-perhydrophenanthrene. It is a typical steroidal compound and an important intermediate in the synthesis of progestogens, adrenocortical hormones, sex hormones, and anabolic steroids. Its production process uses diosgenin as a raw material. After multiple reaction steps, the mother liquor still contains a certain amount of dienes and impurities. Efficient recovery of dienes is crucial to improving resource utilization and reducing production costs.

[0003] In traditional processes, diene mother liquor is usually treated with saponification, extraction, concentration and cooling before being combined with raw materials, but this method has multiple technical bottlenecks. First, impurities such as diene alcohol isomers, polymers and organic acids contained in the mother liquor will significantly interfere with subsequent reactions, resulting in fluctuations in product quality and decreased yields. Secondly, during the saponification process, some dienes are converted into alcohol compounds, and only 30-40% can be reconverted into the target product. The long-term accumulation of remaining by-products affects process stability. The saponin structure in the mother liquor prepared with diosgenin as raw material has similar polar groups to diene alcohol ketone acetate, making it difficult to selectively separate it using traditional extraction or crystallization methods. Residual saponin easily forms co-crystallization or adsorption with dienes, reducing the purity of the recovered product. In addition, traditional methods such as vacuum drying are used to remove residual solvents, which makes it difficult to penetrate the micropores of the crystals, resulting in high residual solvent levels, and high temperatures may destroy the diene structure, affecting product quality stability. Summary of the Invention

[0004] In view of this, the present invention provides a method for recovering diene from diene ketone acetate mother liquor to solve the above problems.

[0005] The technical solution of the present invention is achieved as follows: a method for recovering diene from diene ketone acetate mother liquor comprises the following steps:

[0006] S1, filtering the mother liquor containing dienol ketone acetate through a ceramic membrane to retain impurities with a molecular weight greater than 500 Da to obtain a pretreated mother liquor;

[0007] S2. Add a composite acidifier to the pretreated mother liquor, adjust the pH value gradually at 50-70° C., with the pH drop of ≤0.5 each time, and the total reaction time of 1.5-3 h to obtain an acidified solution;

[0008] S3, adding an extractant to the acidified liquid, extracting under ultrasonic conditions, and separating to obtain an extract phase containing diene;

[0009] S4, reversely washing the extraction phase with a washing liquid, separating the lower layer of washing waste liquid after washing, collecting the upper layer of extraction phase and concentrating it to obtain a crude diene product;

[0010] S5, adding solvent dropwise to the crude diene product in a programmed manner, controlling the cooling rate to 0.5-1°C / min to -15 to -5°C, and crystallizing for 8-12 hours to allow the crude diene product to crystallize uniformly in the solvent, and centrifuging after growing the crystals;

[0011] S6. Wash and dry the crude product obtained by centrifugation with supercritical CO2 fluid to obtain a diene finished product with a purity of ≥99.5%.

[0012] Furthermore, the ceramic membrane in step S1 is a silicon nitride composite membrane, the operating pressure is 0.3-0.8 MPa, and the membrane flux is maintained at ≥80 L / (m 2 h) and protein retention rate>95%.

[0013] Furthermore, the composite acidulant in step S2 is citric acid, aminosulfonic acid and ascorbic acid in a mass ratio of 2:(0.8-1.5):(0.2-0.5).

[0014] Furthermore, during the gradient adjustment in step S2, a composite acidifier is added every 15-20 minutes until the pH value reaches 2.0±0.1.

[0015] Furthermore, the extractant in step S3 is isopropyl acetate and cyclohexane in a volume ratio of 1:3-5.

[0016] Furthermore, in step S3, the ultrasonic frequency is 28-40 kHz, the power is 50-80 W, the extraction temperature is 10-25° C., the extraction time is 15-25 min, and the extraction is repeated 3-4 times.

[0017] Furthermore, the reverse washing in step S4 is performed 2-3 times, and the volume ratio of the extraction phase to the washing liquid is maintained at 1:0.8-1.2 during each washing. The extraction phase and the washing liquid are fully mixed and then allowed to stand for 10-15 minutes to separate the lower layer of washing waste liquid, and the upper layer of the extraction phase is collected and concentrated to a solid content of ≥35% under a vacuum degree ≤-0.095MPa and a temperature ≤45°C. The washing liquid contains a surfactant and a 10-20wt% sodium chloride solution in a mass volume ratio of 0.1-0.5:100, and the surfactant is Tween-80 or Span-60.

[0018] Furthermore, the solvent in step S5 is one or more of cyclohexane, petroleum ether or n-hexane.

[0019] Furthermore, in step S5, the programmed dropwise addition of solvent is controlled according to the following stages:

[0020] Stage 1: 25℃ dropped to 10-15℃, stirring speed 120-180rpm;

[0021] The second stage: 10-15℃ down to -5~5℃, stirring speed 200-300rpm;

[0022] The third stage: -5 ~ 5 ℃ to -15 ~ -5 ℃, stirring speed 80-120 rpm

[0023] Furthermore, the supercritical CO2 fluid washing conditions in step S6 are: pressure 12-18 MPa, temperature 35-45°C, CO2 flow rate 8-12 L / min, the entrainer is an anhydrous ethanol solution containing 0.2-0.5wt% vitamin E, and the volume ratio of the entrainer to supercritical CO2 is 1:50-100.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] Precision filtration using a ceramic membrane with a molecular weight cutoff greater than 500 Da and a protein retention rate greater than 95% efficiently removes large molecular impurities from the mother liquor at room temperature, reducing the impurity content of the pretreated mother liquor. A composite acidifier adjusts the pH gradient, ensuring the gradual release of dienes and minimizing side reactions. Ultrasonic-assisted extraction improves mass transfer, disrupts the interface between dienes and impurities, and accelerates the diffusion of dienes into the extractant. Three-stage programmed crystallization precisely controls supersaturation, resulting in a finished product purity of ≥99.5% and a solvent residue of <10 ppm. Supercritical CO2 scrubbing provides deep impurity removal, while entrainers enhance the solubility of polar impurities, further improving purity. The synergistic combination of technologies throughout the entire process increases the total diene yield to over 73%. This patented technology increases the yield by nearly 5%, and the mother liquor can be recycled, possessing significant industrial application value. DETAILED DESCRIPTION

[0026] In order to better understand the technical content of the present invention, specific examples are provided below to further illustrate the present invention.

[0027] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods.

[0028] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0029] Example 1

[0030] A method for recovering diene from dienol ketone acetate mother liquor comprises the following steps:

[0031] S1. Diosgenin is used as raw material, and after pressure cracking, oxidation, hydrolysis (elimination), extraction, washing and purification, the mother liquor of diosgenin acetate is obtained. The mother liquor is filtered through a silicon nitride composite membrane, and the impurities with a molecular weight cutoff of more than 500Da are retained. The operating pressure is 0.3MPa, and the membrane flux is maintained at ≥80L / (m 2 h) and the protein retention rate is greater than 95%, to obtain a pretreated mother liquor;

[0032] S2, adding a composite acidulant to the pretreated mother liquor, the composite acidulant being citric acid, sulfamic acid and ascorbic acid in a mass ratio of 2:0.8:0.2, the pH drop being ≤0.5 each time, the composite acidulant being added at intervals of 15 min at 50 ° C. and gradient adjustment being performed until the pH value reaches 1.9, the total reaction time being 1.5 h, to obtain an acidified solution;

[0033] S3, adding an extractant to the acidified liquid, wherein the extractant is isopropyl acetate and cyclohexane in a volume ratio of 1:3, and extracting under ultrasound, the ultrasonic frequency is 28 kHz, the power is 50 W, the extraction temperature is 10 ° C, the extraction time is 15 min, and the extraction is repeated 3 times to separate the extract phase containing diene;

[0034] S4, the extraction phase is reversely washed with a washing liquid, the washing times are 2 times, the washing liquid mass volume ratio is 0.1:100 surfactant and 10wt% sodium chloride solution, the surfactant is Tween-80, and the volume ratio of the extraction phase to the washing liquid is maintained at 1:0.8 during each washing. The extraction phase and the washing liquid are fully mixed and then allowed to stand for 10 minutes to separate the lower washing waste liquid, and the upper extraction phase is collected and concentrated to a solid content of ≥35% under a vacuum degree of ≤-0.095 MPa and a temperature of ≤45°C to obtain a crude diene;

[0035] S5. Add n-hexane dropwise to the crude diene product, control the cooling rate to 0.5°C / min, and crystallize for 8 hours. Program crystallization:

[0036] Stage 1: 25°C to 10°C, stirring speed 120 rpm, time 2.5 hours;

[0037] The second stage: 10℃ down to -5℃, stirring speed 200rpm, time 3 hours;

[0038] The third stage: -5℃ to -15℃, stirring speed 80rpm, 2.5 hours.

[0039] S6. Wash and dry the crude product obtained by centrifugation with supercritical CO2 fluid, wherein the CO2 fluid washing conditions are: pressure 12 MPa, temperature 35°C, CO2 flow rate 8 L / min, entrainer an anhydrous ethanol solution containing 0.2 wt% vitamin E, and the volume ratio of entrainer to supercritical CO2 is 1:50; obtain a diene finished product with a purity of ≥99.5%.

[0040] Example 2

[0041] A method for recovering diene from dienol ketone acetate mother liquor comprises the following steps:

[0042] S1. Diosgenin is used as raw material, and after pressure cracking, oxidation, hydrolysis (elimination), extraction, washing and purification, the mother liquor of diosgenin acetate is obtained. The mother liquor is filtered through a silicon nitride composite membrane, and the impurities with a molecular weight cutoff of more than 500Da are retained. The operating pressure is 0.8MPa, and the membrane flux is maintained at ≥80L / (m 2 h) and the protein retention rate is greater than 95%, to obtain a pretreated mother liquor;

[0043] S2. Add a composite acidulant to the pretreated mother liquor, wherein the composite acidulant is citric acid, sulfamic acid and ascorbic acid in a mass ratio of 2:1.5:0.5, and adjust the pH value by gradient at 70° C., with each pH drop of ≤0.5, and add the composite acidulant every 20 min until the pH value reaches 2.1, with a total reaction time of 3 h, to obtain an acidified solution;

[0044] S3, adding an extractant to the acidified solution, wherein the extractant is isopropyl acetate and cyclohexane in a volume ratio of 1:5, and extracting under ultrasound, the ultrasonic frequency is 40kHz, the power is 80W, the extraction temperature is 25°C, the extraction time is 25min, and the extraction is repeated 4 times to separate the extract phase containing diene;

[0045] S4, the extract phase is reversely washed with a washing liquid for 3 times, the washing liquid mass volume ratio of 0.5:100 surfactant and 20wt% sodium chloride solution, the surfactant is Span-60, and the volume ratio of the extract phase to the washing liquid is maintained at 1:1.2 during each washing. The extract phase and the washing liquid are fully mixed and then allowed to stand for 15 minutes to separate the lower washing waste liquid, and the upper extract phase is collected and concentrated to a solid content of ≥35% under a vacuum degree of ≤-0.095 MPa and a temperature of ≤45°C to obtain a crude diene;

[0046] S5. Add n-hexane dropwise to the crude diene product, control the cooling rate to 1°C / min, and crystallize for 12 hours. Program crystallization:

[0047] Stage 1: 25°C to 15°C, stirring speed 180 rpm, time 3 hours;

[0048] The second stage: 15℃ down to 5℃, stirring speed 300rpm, time 5 hours;

[0049] The third stage: 5℃ to -5℃, stirring speed 120rpm, 4 hours.

[0050] S6. Wash and dry the crude product obtained by centrifugation with supercritical CO2 fluid, wherein the CO2 fluid washing conditions are: pressure 18 MPa, temperature 45°C, CO2 flow rate 12 L / min, entrainer an anhydrous ethanol solution containing 0.5 wt% vitamin E, and the volume ratio of entrainer to supercritical CO2 is 1:100; obtain a diene finished product with a purity ≥99.5%.

[0051] Example 3

[0052] A method for recovering diene from dienol ketone acetate mother liquor comprises the following steps:

[0053] S1. Diosgenin is used as raw material, and after pressure cracking, oxidation, hydrolysis (elimination), extraction, washing and purification, the mother liquor of diosgenin acetate is obtained. The mother liquor is filtered through a silicon nitride composite membrane, and the impurities with a molecular weight cutoff of more than 500Da are retained. The operating pressure is 0.5MPa, and the membrane flux is maintained at ≥80L / (m 2 h) and the protein retention rate is greater than 95%, to obtain a pretreated mother liquor;

[0054] S2. Add a composite acidulant to the pretreated mother liquor, wherein the composite acidulant is citric acid, sulfamic acid and ascorbic acid in a mass ratio of 2:1.2:0.3, and adjust the pH value by gradient at 60°C, with each pH drop of ≤0.5, and add the composite acidulant every 18 minutes until the pH value reaches 2.0, with a total reaction time of 2.5 hours to obtain an acidified solution;

[0055] S3, adding an extractant to the acidified solution, the extractant is isopropyl acetate and cyclohexane in a volume ratio of 1:4, and extracting under ultrasound, the ultrasonic frequency is 32kHz, the power is 70W, the extraction temperature is 18°C, the extraction time is 20min, and the extraction is repeated 3 times to separate the extract phase containing diene;

[0056] S4, the extraction phase is reversely washed with a washing liquid for 3 times, the washing liquid mass volume ratio is 0.3:100 surfactant and 15wt% sodium chloride solution, the surfactant is Tween-80, and the volume ratio of the extraction phase to the washing liquid is maintained at 1:1 during each washing. The extraction phase and the washing liquid are fully mixed and then allowed to stand for 12 minutes to separate the lower washing waste liquid, and the upper extraction phase is collected and concentrated to a solid content of ≥35% under a vacuum degree of ≤-0.095 MPa and a temperature of ≤45°C to obtain a crude diene;

[0057] S5. Add n-hexane dropwise to the crude diene product, control the cooling rate to 0.8°C / min, and crystallize for 10 hours. Program crystallization:

[0058] Stage 1: 25°C to 12°C, stirring speed 150 rpm, time 3 hours;

[0059] The second stage: 12℃ to 0℃, stirring speed 250rpm, time 4 hours;

[0060] The third stage: 0°C to -10°C, stirring speed 100 rpm, 3 hours.

[0061] S6. Wash and dry the crude product obtained by centrifugation with supercritical CO2 fluid, wherein the CO2 fluid washing conditions are: pressure 15 MPa, temperature 40°C, CO2 flow rate 10 L / min, entrainer an anhydrous ethanol solution containing 0.4 wt% vitamin E, and the volume ratio of entrainer to supercritical CO2 is 1:80; obtain a diene finished product with a purity ≥99.5%.

[0062] Comparative Example 1

[0063] The difference between this comparative example and Example 3 is that step S2 is omitted and no composite acidifier is added to the pretreated mother liquor;

[0064] The pretreated mother liquor is directly added into the extractant for extraction.

[0065] Comparative Example 2

[0066] The difference between this comparative example and Example 3 is that hydrochloric acid is used instead of the composite acidifying agent, the pH is directly adjusted to 2.0 without a gradient adjustment process, and the reaction time is 2.5 h.

[0067] Comparative Example 3

[0068] The difference between this comparative example and Example 3 is that the extraction in step S3 is not assisted by ultrasound.

[0069] Comparative Example 4

[0070] The difference between this comparative example and Example 3 is that in step S5, n-hexane is added to the crude diene product at one time to reduce the temperature to -10°C, and crystallize for 10 hours without staged programmed control.

[0071] Comparative Example 5

[0072] The difference between this comparative example and Example 3 is that supercritical CO2 washing is omitted in step S6 and vacuum drying (60°C, -0.09 MPa) is adopted. The remaining steps are the same as in Example 3.

[0073] 1. Effect Verification

[0074] In the methods for recovering dienes according to Examples 1-3 and Comparative Examples 1-5, the diene purity, total yield, saponin residue, and n-hexane residue of each group were tested.

[0075] (1) Product purity determination: HPLC method (chromatographic column: C18, mobile phase methanol-water gradient elution);

[0076] (2) Calculation of total yield: mass of diene finished product / theoretical yield × 100%;

[0077] (3) Saponin residue detection: HPLC-MS method (ion source: ESI+);

[0078] (4) Solvent residue: GC-FID method was used to determine the residual n-hexane;

[0079] Test results:

[0080]

[0081]

[0082] Result analysis: The present invention achieves impurity removal, high diene yield and low solvent residue through the synergistic effect of four technologies: gradient acidification, ultrasonic enhanced extraction, programmed crystallization and supercritical washing.

[0083] Comparison of Example 3 with Comparative Examples 1 and 2:

[0084] The unacidified mother liquor contains a large amount of water-soluble impurities, including unreacted saponin derivatives and proteins. These impurities form stable complexes with dienes and cannot be effectively separated by extraction. As a result, the impurities enter the product with the extract phase. At the same time, the dienes are not completely released, resulting in a sharp increase in saponin residues and a significant reduction in yield.

[0085] In Comparative Example 2, hydrochloric acid alone cannot effectively complex or decompose various impurities in the mother liquor, and there is no gradient adjustment, which will lead to local overacidity and cause diene hydrolysis or oxidation side reactions, resulting in reduced yield and purity.

[0086] The results show that the gradient adjustment of the composite acidifier of the present invention enables citric acid to complex metal ions and reduce the combination of impurities and dienes through synergistic effect; aminosulfonic acid slowly releases hydrogen ions to avoid local overacidity; ascorbic acid resists oxidation and protects the diene structure; and the gradient adjustment ensures the gradual release of diene and reduces side reactions.

[0087] Comparison with Comparative Example 3 shows that ultrasound generates microjets through cavitation effect, destroys the interface layer between diene and impurities, and accelerates the diffusion of diene into the extractant; at the same time, the mechanical vibration of ultrasound can reduce the stratification resistance between the extractant and the mother liquor, thereby improving the extraction efficiency.

[0088] Compared with Comparative Example 4, adding the solvent all at once and rapidly cooling the mixture results in an instantaneous increase in crystallization supersaturation. The nucleation rate is much greater than the growth rate, resulting in a large number of fine crystals with a large specific surface area, which are prone to entrapment of solvent and impurities. Furthermore, the crystals are uneven in size, and fine crystals easily pass through the filter cloth during centrifugation, resulting in a decrease in yield. However, adding the solvent and cooling the mixture in three stages effectively optimizes the crystal growth kinetics. In the first stage, nucleation is slowed at low supersaturation, reducing the number of nuclei. In the second stage, moderate supersaturation promotes crystal growth and forms a uniform particle size. In the third stage, low supersaturation is used to grow the crystals, reducing entrapment. The resulting crystals have a uniform particle size and smooth surface, with residual solvent and impurities less than 10 ppm and a yield of ≥73%, reaching the theoretical yield level.

[0089] Compared with Comparative Example 5, vacuum drying only removes the solvent by heating and reducing pressure, but a small amount of solvent and trace impurities may remain in the micropores and between the crystals of the diene crystals and cannot be completely removed; while supercritical CO2 has liquid-like solubility and gas-like diffusivity, and can penetrate into the interior of the crystal, dissolve and carry away residual solvent and impurities; at the same time, the entrainer can enhance the solubility of polar impurities and further improve the purity.

[0090] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for recovering diene from dienol ketone acetate mother liquor, characterized in that: The following steps are involved: S1, filtering the mother liquor containing dienol ketone acetate to retain impurities with a molecular weight greater than 500 Da to obtain a pretreated mother liquor; S2. Add a composite acidifier to the pretreated mother liquor, adjust the pH value gradually at 50-70° C., with the pH drop of ≤0.5 each time, and the total reaction time of 1.5-3 h to obtain an acidified solution; S3, adding an extractant to the acidified liquid, extracting under ultrasonic conditions, and separating to obtain an extract phase containing diene; S4, reversely washing the extract phase with a washing liquid, separating the lower washing waste liquid after washing, collecting the upper extract phase and concentrating it to obtain a crude diene; S5. Add solvent dropwise to the crude diene product in a programmed manner, cool to -15 to -5°C, and crystallize for 8 to 12 hours to allow the crude diene product to crystallize uniformly in the solvent, grow the crystals, and then centrifuge; S6. The crude product obtained by centrifugation is washed and dried with supercritical CO2 fluid to obtain a diene product.

2. The method for recovering diene from a diene ketone acetate mother liquor according to claim 1, wherein: The ceramic membrane in step S1 is a silicon nitride composite membrane, the operating pressure is 0.3-0.8 MPa, and the membrane flux is maintained at ≥80 L / (m 2 h) and protein retention rate>95%.

3. The method for recovering diene from a diene ketone acetate mother liquor according to claim 1, wherein: The composite acidulant in step S2 is citric acid, aminosulfonic acid and ascorbic acid in a mass ratio of 2: (0.8-1.5): (0.2-0.5).

4. The method for recovering diene from a diene ketone acetate mother liquor according to claim 1, wherein: During the gradient adjustment in step S2, the composite acidifier is added every 15-20 minutes until the pH value reaches 2.0±0.

1.

5. The method for recovering diene from dienolone acetate mother liquor according to claim 1, wherein: The extractant in step S3 is isopropyl acetate and cyclohexane in a volume ratio of 1:3-5.

6. The method for recovering diene from dienolone acetate mother liquor according to claim 1, wherein: In step S3, the ultrasonic frequency is 28-40 kHz, the power is 50-80 W, the extraction temperature is 10-25° C., the extraction time is 15-25 min, and the extraction is repeated 3-4 times.

7. The method for recovering diene from dienolone acetate mother liquor according to claim 1, wherein: The reverse washing in step S4 is performed 2-3 times, and the volume ratio of the extraction phase to the washing liquid is maintained at 1:0.8-1.2 during each washing. The extraction phase and the washing liquid are fully mixed and then allowed to stand for stratification for 10-15 minutes, and the lower layer of washing waste liquid is separated. The upper layer of the extraction phase is collected and concentrated to a solid content of ≥35% under a vacuum degree ≤-0.095MPa and a temperature ≤45°C. The washing liquid contains a surfactant and a 10-20wt% sodium chloride solution in a mass volume ratio of 0.1-0.5:100, and the surfactant is Tween-80 or Span-60.

8. The method for recovering diene from dienolone acetate mother liquor according to claim 1, wherein: The solvent in step S5 is one or more of cyclohexane, petroleum ether or n-hexane.

9. The method for recovering diene from dienolone acetate mother liquor according to claim 1, wherein: In step S5, the solvent is added dropwise in a programmed manner, with 0.5-1.5 mL added each time, and the process is controlled in the following stages: Stage 1: 25℃ dropped to 10-15℃, stirring speed 120-180rpm; The second stage: 10-15℃ down to -5~5℃, stirring speed 200-300rpm; The third stage: -5~5℃ dropped to -15~-5℃, stirring speed 80-120rpm.

10. The method for recovering diene from dienolone acetate mother liquor according to claim 1, wherein: The supercritical CO2 fluid washing conditions in step S6 are: pressure 12-18 MPa, temperature 35-45°C, CO2 flow rate 8-12 L / min, the entrainer is an anhydrous ethanol solution containing 0.2-0.5wt% vitamin E, and the volume ratio of the entrainer to supercritical CO2 is 1:50-100.

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