A method for recovering mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof

Abstract

This invention discloses a method for recovering the mother liquor after purifying crude vitamin D3 or its metabolic derivatives. The method includes the following steps: After evaporating the solvent from the mother liquor of crude cholecalciferol or calcidiol, an oily concentrate is obtained. This concentrate is then added to a high-boiling-point oil and mixed thoroughly. Cholecalciferol or calcidiol is then collected and recovered using molecular distillation technology. This invention utilizes molecular distillation technology to efficiently recover cholecalciferol or calcidiol, increasing the cholecalciferol or calcidiol content in the cholecalciferol or calcidiol resin oil to over 80%, with a recovery rate of over 90%. Furthermore, the process is simple, has a short flow, and involves only physical separation without the addition of any harmful chemicals.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of separation and purification technology, and particularly relates to a method for recovering cholecalciferol from mother liquor after purification of crude vitamin D3 or its metabolic derivative, which is suitable for the pharmaceutical, food and health product industries. BACKGROUND

[0002] Vitamin D3 (cholecalciferol) is mainly synthesized by the skin under ultraviolet B (UVB) irradiation, and can also be obtained through food and supplements. The main function of cholecalciferol is to help the intestinal absorption of calcium and phosphorus, maintain bone health, and prevent rickets and osteoporosis. With further research on cholecalciferol, it has also been shown to play an important role in immune regulation and chronic disease prevention. Calcifediol (25-hydroxyvitamin D3) is a metabolic derivative of vitamin D3. Compared with vitamin D3, it has increased hydrophilicity due to the addition of a hydroxyl group, making it more easily circulated in the blood, with a biological activity of 3-5 times that of vitamin D3, and it is more easily absorbed into the blood circulation from the intestinal tract. Calcifediol has a significant effect on metabolic bone diseases such as osteoporosis, rickets, and osteomalacia, and can also be used to treat hypocalcemia caused by hemodialysis. It can also be used as a health food raw material and a feed additive, and has a wide range of applications in health food, pharmaceuticals, and feed additives.

[0003] Currently, there are few processes reported in the literature for the reuse of mother liquor after the separation and purification of vitamin D3 and its metabolic derivatives. Patent CN114380726A uses the mother liquor after purification as a raw material, converts the phytosterol in it into previtamin D3 through a photochemical reaction, and then generates vitamin D3 through a thermal isomerization reaction, thereby increasing the content of vitamin D3 in the mother liquor. Patent CN110527700A relates to two kinds of crystallization mother liquor. The first one: vitamin D3 crude product is subjected to esterification to obtain vitamin D3 ester, and the mother liquor after crystallization of the vitamin D3 ester is concentrated, saponified, and then subjected to thermal isomerization to obtain feed-grade vitamin D3. The second one: vitamin D3 ester crystals are saponified, extracted, and crystallized to obtain vitamin D3 fine product, and the mother liquor after crystallization is concentrated and subjected to thermal isomerization to be reused as a substrate. Patent CN103044301A uses 25-hydroxy-7-dehydrocholesterol as a raw material, separates and recovers 25-hydroxy-7-dehydrocholesterol after irradiation, and then subjects the remaining reaction material to thermal isomerization after recovery of the raw material, and then performs recrystallization to obtain calcifediol. The mother liquor produced after crystallization and purification still contains residual products, intermediate products, and by-products. SUMMARY

[0004] In order to solve the problems in the prior art, the present application aims at a method for recovering mother liquor after purification of crude vitamin D3 or its metabolic derivative, which uses molecular distillation technology to improve the content of cholecalciferol or calcifediol in the mother liquor after purification of crude product, maximizes cholecalciferol or calcifediol pure product, and thus improves economic benefits.

[0005] To achieve the above-mentioned purpose, the present application provides a method for recovering mother liquor after purification of crude vitamin D3 or its metabolic derivative, which comprises the following steps:

[0006] (1) obtaining an oily concentrate after evaporating the solvent from the mother liquor after purification of crude cholecalciferol or calcifediol;

[0007] (2) dissolving the oily concentrate in high-boiling-point oil and mixing uniformly;

[0008] (3) collecting and recovering cholecalciferol or calcifediol resin oil from the high-boiling-point oil solution mixed with the oily concentrate by using molecular distillation technology.

[0009] The purity of cholecalciferol or calcifediol resin oil collected by molecular distillation is improved from 5-50wt% to more than 80wt% after HPLC detection, and the recovery rate of cholecalciferol or calcifediol is more than 90wt%.

[0010] Further, in the step (1), the mother liquor after separation and purification of cholecalciferol or calcifediol refers to cholecalciferol or calcifediol crude product which is obtained by one or more combined processes of multiple refining processes, including extraction, column chromatography, chemical purification and crystallization, wherein at least a crystallization process is included, and the crystallization process is the final refining step, which is performed by subjecting high-purity cholecalciferol or calcifediol solid to operations including dissolution, crystallization and solid-liquid separation in a specific solvent system, and finally obtaining cholecalciferol or calcifediol pure product meeting the standard of pharmacopoeia, while producing cholecalciferol or calcifediol mother liquor containing residual active ingredients. The raw material used in the present application is the cholecalciferol or calcifediol mother liquor produced after the crystallization process is completed.

[0011] Further, in the step (1), the content of cholecalciferol or calcifediol in the oily concentrate is 5-50wt%.

[0012] Further, in the step (1), the conditions for evaporating the solvent from the mother liquor are temperature 30-80℃ and vacuum ≤-0.05 MPa; preferably, the temperature is 50-70℃ and the vacuum is ≤-0.08 MPa.

[0013] Further, in the step (2), the high-boiling-point oil is mineral oil or vegetable oil.

[0014] Further, in the step (2), the mineral oil is liquid paraffin or solid paraffin, preferably solid paraffin.

[0015] Further, in the step (2), the vegetable oil is one or more of rapeseed oil, soybean oil, cottonseed oil, sunflower seed oil, peanut oil, palm oil, corn oil, sesame oil, flaxseed oil, rice oil, tea oil, olive oil.

[0016] Further, in the step (2), the high-boiling oil is generally used in an amount of 1-10 mL / g of the concentrate, preferably 4-6 mL / g.

[0017] Further, in the step (3), the molecular distillation technology is first-stage molecular distillation to remove low-boiling substances, second-stage molecular distillation to obtain cholecalciferol or calcifediol resin oil, or second-stage molecular distillation to remove slightly lower boiling impurities, and third-stage molecular distillation to collect cholecalciferol or calcifediol resin oil.

[0018] Further, in the step (3), the first-stage molecular distillation of the pretreated mother liquor is controlled at a distillation pressure of 50-80 Pa, preferably a pressure of 60-70 Pa.

[0019] Further, in the step (3), the first-stage molecular distillation of the pretreated mother liquor is adjusted to a feed flow rate of 5-20 g / min and a molecular distillation scraper rotation speed of 150-300 rpm.

[0020] Further, in the step (3), the first-stage molecular distillation of the pretreated mother liquor is controlled at a preheating temperature of 30-60℃, a distillation temperature of 70-100℃, and a condensation temperature of 30-50℃; preferably a preheating temperature of 60-70℃, a distillation temperature of 80-90℃, and a condensation temperature of 35-45℃.

[0021] Further, in the step (3), the second-stage molecular distillation of the heavy phase obtained from the first-stage molecular distillation product is controlled at a distillation pressure of 5-20 Pa, preferably a pressure of 10-15 Pa.

[0022] Further, in the step (3), the second-stage molecular distillation of the heavy phase obtained from the first-stage molecular distillation product is controlled at a molecular distillation scraper rotation speed of 180-300 rpm.

[0023] Further, in the step (3), the second-stage molecular distillation of the heavy phase obtained from the first-stage molecular distillation product is controlled at a preheating temperature of 50-80℃, a distillation temperature of 170-240℃, and a condensation temperature of 50-100℃; preferably a preheating temperature of 55-70℃, a distillation temperature of 180-220℃, and a condensation temperature of 70-80℃.

[0024] Further, in the step (3), the heavy phase obtained from the secondary molecular distillation product is subjected to a third molecular distillation, and the distillation pressure is controlled to be 0-1 Pa; preferably, the pressure is 0-0.5 Pa.

[0025] Further, in the step (3), the heavy phase obtained from the secondary molecular distillation product is subjected to a third molecular distillation, and the molecular distillation scraper rotating speed is controlled to be 200-300 rpm.

[0026] Further, in the step (3), the heavy phase obtained from the secondary molecular distillation product is subjected to a third molecular distillation, and the preheating temperature is controlled to be 50-80 DEG C, the distillation temperature is controlled to be 210-280 DEG C, and the condensation temperature is controlled to be 70-100 DEG C; preferably, the preheating temperature is 55-70 DEG C, the distillation temperature is 220-270 DEG C, and the condensation temperature is 75-95 DEG C.

[0027] Further, the mass percentage content of cholecalciferol or calcifediol after the molecular distillation is above 80%. The obtained cholecalciferol crude product is subjected to separation and purification and crystallization to obtain cholecalciferol or calcifediol pure product.

[0028] Compared with the prior art, the present application has the following beneficial effects:

[0029] In the prior art, for the mother liquor concentrate produced in the cholecalciferol separation and purification process, the conventional treatment method usually adopts two paths: one method is to reuse the material as a raw material to the front process, but this method is complex in operation and large in solvent consumption; the other method is to convert into a feed grade raw material for use, but this method has the disadvantages of many impurities, unverified biological safety, etc. Therefore, the present application directly improves the content of cholecalciferol in the mother liquor by using molecular distillation technology, and uses the cholecalciferol crude product as a raw material for the next step of crystallization to obtain cholecalciferol pure product, which can maximize the green benefit, avoid potential risks, fully utilize the value of process products, and improve economic benefits.

[0030] The calcifediol resin oil obtained by the present application can be used in the calcifediol crude product crystallization process, thereby improving the yield of calcifediol and reducing the consumption of raw materials. The research on the reuse of calcifediol mother liquor not only improves the production efficiency but also reduces the production cost, which is an important path to realize green manufacturing and sustainable development; and the research on the reuse of calcifediol mother liquor after crystallization helps to perfect the whole process closed loop system of calcifediol production and provides technical reference for green production of the industry. DETAILED DESCRIPTION

[0031] In order to make the technical scheme and advantages of the present application clearer, the present application will be further described in detail below with reference to examples. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application.

[0032] Example 1

[0033] The mother liquor after separation and purification of cholecalciferol was evaporated at 55°C under vacuum-0.08 MPa to remove the solvent, and 1 kg of oil concentrate (cholecalciferol content 8.6%) was obtained. 2 L of dissolved solid paraffin was added and mixed uniformly at 70°C, and the mixture was incubated at 70°C. The mixture was then fed into a two-stage molecular distillation device at a feed rate of 10 mL / min through a feedstock, with a first-stage system pressure of 50 pa, a wiped-film rotor speed of 150 rpm, a distillation temperature of 70°C, and a condensation temperature of 35°C. The light phase, which contained small molecular hydrocarbons, was collected and fed into a two-stage molecular distillation device at a heavy phase incubated at 60°C. The two-stage system had a pressure of 0.4 pa, a wiped-film rotor speed of 200 rpm, a distillation temperature of 245°C, and a condensation temperature of 80°C. The light phase collected was cholecalciferol resin oil, with a cholecalciferol content of 86.6% and a total weight of 92.6 g, and the recovery rate was 93.2%.

[0034] Example 2

[0035] The mother liquor after separation and purification of cholecalciferol was evaporated at 55°C under vacuum-0.08 MPa to remove the solvent, and 1 kg of oil concentrate (cholecalciferol content 8.6%) was obtained. 2 L of dissolved solid paraffin was added and mixed uniformly at 70°C, and the mixture was incubated at 70°C. The mixture was then fed into a two-stage molecular distillation device at a feed rate of 10 mL / min through a feedstock, with a first-stage system pressure of 50 pa, a wiped-film rotor speed of 150 rpm, a distillation temperature of 70°C, and a condensation temperature of 35°C. The light phase, which contained small molecular hydrocarbons, was collected and fed into a two-stage molecular distillation device at a heavy phase incubated at 60°C. The two-stage system had a pressure of 0.4 pa, a wiped-film rotor speed of 200 rpm, a distillation temperature of 245°C, and a condensation temperature of 80°C. The light phase collected was cholecalciferol resin oil, with a cholecalciferol content of 86.6% and a total weight of 92.6 g, and the recovery rate was 93.2%.

[0036] Example 3

[0037] The mother liquor after separation and purification of cholecalciferol was evaporated at 55°C under vacuum-0.08 MPa to remove the solvent, and 1 kg of oil concentrate (cholecalciferol content 24.8%) was obtained. 4 L of peanut oil was added and mixed evenly, and the mixture was kept at 55°C and then fed into a three-stage molecular distillation device. The pressure of the first-stage system was 50 pa, the scraping rotor speed was 160 rpm, the feeding rate was 15 mL / min, the distillation temperature was controlled at 75°C, and the condensation temperature was 40°C. The light phase containing small molecular hydrocarbons and low carbon chain fatty acids was collected, and the heavy phase kept at 60°C was fed into the second-stage molecular distillation. The pressure of the second-stage system was 15 pa, the scraping rotor speed was 200 rpm, the distillation temperature was controlled at 180°C, and the condensation temperature was 75°C. The light phase containing steryl esters, luminsterol and long carbon chain fatty acids was collected, and the heavy phase kept at 60°C was fed into the third-stage molecular distillation. The pressure of the third-stage system was 0.5 pa, the scraping rotor speed was 240 rpm, the distillation temperature was 230°C, and the condensation temperature was 75°C. The light phase collected was cholecalciferol resin oil, the cholecalciferol content was 91.6%, and the total amount was 255.9 g, with a recovery rate of 94.5%.

[0038] Example 4

[0039] The mother liquor after separation and purification of cholecalciferol was evaporated at 55°C under vacuum-0.08 MPa to remove the solvent, and 1 kg of oil concentrate (cholecalciferol content 24.8%) was obtained. 4 L of peanut oil was added and mixed evenly, and the mixture was kept at 55°C and then fed into a three-stage molecular distillation device. The pressure of the first-stage system was 50 pa, the scraping rotor speed was 160 rpm, the feeding rate was 15 mL / min, the distillation temperature was controlled at 75°C, and the condensation temperature was 40°C. The light phase containing small molecular hydrocarbons and low carbon chain fatty acids was collected, and the heavy phase kept at 60°C was fed into the second-stage molecular distillation. The pressure of the second-stage system was 15 pa, the scraping rotor speed was 200 rpm, the distillation temperature was controlled at 180°C, and the condensation temperature was 75°C. The light phase containing steryl esters, luminsterol and long carbon chain fatty acids was collected, and the heavy phase kept at 60°C was fed into the third-stage molecular distillation. The pressure of the third-stage system was 0.5 pa, the scraping rotor speed was 240 rpm, the distillation temperature was 230°C, and the condensation temperature was 75°C. The light phase collected was cholecalciferol resin oil, the cholecalciferol content was 91.6%, and the total amount was 255.9 g, with a recovery rate of 94.5%.

[0040] Example 5

[0041] The mother liquor after separation and purification of calcifediol is evaporated at 55°C under vacuum-0.08 MPa to remove the solvent, and 1.2 kg of oil concentrate (calcifediol content 8%) is obtained. The oil concentrate is mixed with 4.8 L of peanut oil, and the mixture is kept at 60°C. The mixture is fed into a three-stage molecular distillation device at a feed rate of 10 mL / min through a feeder, and the distillation temperature is controlled at 75°C, and the condensation temperature is controlled at 40°C. The light phase is collected, and the heavy phase is kept at 60°C and fed into a two-stage molecular distillation device. The two-stage molecular distillation device is operated at a system pressure of 10 pa, a wiped-film rotor speed of 200 rpm, a distillation temperature of 200°C, and a condensation temperature of 90°C. The light phase is collected, and the heavy phase is kept at 80°C and fed into a three-stage molecular distillation device. The three-stage molecular distillation device is operated at a system pressure of 0.5 pa, a wiped-film rotor speed of 200 rpm, a distillation temperature of 260°C, and a condensation temperature of 95°C. The collected light phase is calcifediol resin oil, and the calcifediol content is 88%, and the total amount of the calcifediol resin oil is 103.94 g, and the recovery rate is 95.28%.

[0042] Example 6

[0043] The mother liquor after separation and purification of calcifediol is evaporated at 55°C under vacuum-0.08 MPa to remove the solvent, and 1.0 kg of oil concentrate (calcifediol content 26%) is obtained. The oil concentrate is mixed with 6.0 L of rapeseed oil, and the mixture is kept at 60°C. The mixture is fed into a three-stage molecular distillation device at a feed rate of 15 mL / min through a feeder, and the distillation temperature is controlled at 75°C, and the condensation temperature is controlled at 40°C. The light phase is collected, and the heavy phase is kept at 60°C and fed into a two-stage molecular distillation device. The two-stage molecular distillation device is operated at a system pressure of 15 pa, a wiped-film rotor speed of 200 rpm, a distillation temperature of 210°C, and a condensation temperature of 90°C. The light phase is collected, and the heavy phase is kept at 80°C and fed into a three-stage molecular distillation device. The three-stage molecular distillation device is operated at a system pressure of 0.8 pa, a wiped-film rotor speed of 200 rpm, a distillation temperature of 270°C, and a condensation temperature of 95°C. The collected light phase is calcifediol resin oil, and the calcifediol content is 83%, and the total amount of the calcifediol resin oil is 292.89 g, and the recovery rate is 93.5%.

[0044] The above-described embodiments are only a preferred scheme of the present application, and do not limit the present application in any form. Other variants and modifications can be made without departing from the technical scheme recited in the claims.

Claims

1. A method for recovering mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof, characterized in that, The method comprises the following steps: (1) After the solvent of the mother liquor of crude cholecalciferol or calcifediol is evaporated, an oily concentrate is obtained; (2) The oily concentrate is added to high-boiling oil for dissolution and uniform mixing; the high-boiling oil is mineral oil or vegetable oil; the mineral oil is liquid paraffin or solid paraffin; the vegetable oil is one or more of rapeseed oil, soybean oil, cottonseed oil, sunflower seed oil, peanut oil, palm oil, corn oil, sesame oil, flaxseed oil, rice oil, tea oil, and olive oil; (3) The high-boiling oil solution mixed with the oily concentrate is collected to recover cholecalciferol or calcifediol resin oil by using a molecular distillation technology; the molecular distillation technology is that low-boiling substances are removed by first-stage molecular distillation, cholecalciferol or calcifediol resin oil is obtained by second-stage molecular distillation, or impurities with slightly lower boiling points are removed by second-stage molecular distillation, and cholecalciferol or calcifediol resin oil is collected by third-stage molecular distillation.

2. A method for recovering the mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof according to claim 1, characterized in that, In step (1), the content of cholecalciferol or calcifediol in the oily concentrate is 5-50%.

3. A method for recovering the mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof according to claim 1, characterized in that, The high-boiling oil solution mixed with the oily concentrate is subjected to first-stage molecular distillation, the distillation pressure is controlled to be 50-80 Pa, the feeding flow rate is controlled to be 10-20 g / min, and the molecular distillation scraper speed is controlled to be 150-200 rpm.

4. The method of claim 1, wherein the method is characterized by, The high-boiling oil solution mixed with the oily concentrate is subjected to first-stage molecular distillation, the preheating temperature is controlled to be 45-60℃, the distillation temperature is controlled to be 70-80℃, and the condensation temperature is controlled to be 30-50℃.

5. The method of recovering the mother liquor after purification of crude vitamin D3 or its metabolic derivatives according to claim 1, characterized in that, The heavy phase obtained from the first-stage molecular distillation product is subjected to second-stage molecular distillation, and the second-stage molecular distillation is controlled, the distillation pressure is controlled to be 0-1 Pa, and the molecular distillation scraper speed is controlled to be 200-280 rpm.

6. The method of recovering the mother liquor after purification of crude vitamin D3 or its metabolic derivatives according to claim 1, characterized in that, The heavy phase obtained from the first-stage molecular distillation product is subjected to second-stage molecular distillation, and the second-stage molecular distillation is controlled, the preheating temperature is controlled to be 50-70℃, the distillation temperature is controlled to be 210-250℃, and the condensation temperature is controlled to be 70-80℃.

7. A method for recovering the mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof according to claim 1, characterized in that, The heavy phase obtained from the first-stage molecular distillation product is subjected to second-stage molecular distillation, and the third-stage molecular distillation is controlled, the distillation pressure is controlled to be 5-20 Pa, and the molecular distillation scraper speed is controlled to be 180-250 rpm.

8. A method for recovering the mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof according to claim 1, characterized in that, The heavy phase obtained from the first-stage molecular distillation product is subjected to second-stage molecular distillation, and the third-stage molecular distillation is controlled, the preheating temperature is controlled to be 50-70℃, the distillation temperature is controlled to be 170-200℃, and the condensation temperature is controlled to be 70-80℃.

9. A method for recovering the mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof according to claim 1, characterized in that, The heavy phase obtained from the second-stage molecular distillation product is subjected to third-stage molecular distillation, the distillation pressure is controlled to be 0-1 Pa, and the molecular distillation scraper speed is controlled to be 200-280 rpm.

10. A method for recovering the mother liquor after purification of crude vitamin D3 or a metabolic derivative thereof according to claim 1, characterized in that, The heavy phase obtained from the second-stage molecular distillation product is subjected to third-stage molecular distillation, the preheating temperature is controlled to be 50-70℃, the distillation temperature is controlled to be 210-250℃, and the condensation temperature is controlled to be 70-80℃.