A purification method for low-content ivermectin recovery powder

Abstract

This invention discloses a purification method for low-content ivermectin recovered powder, belonging to the field of pharmaceutical technology. The method includes the following steps: dissolving secondary ivermectin recovered powder in an ethanol-water solution, heating, stirring at a constant temperature, cooling, and filtering to obtain tertiary recovered powder; dissolving the tertiary recovered powder in an ethanol-water solution, cooling, crystallizing, and filtering to obtain quaternary recovered powder and quaternary recovered mother liquor; using the quaternary recovered mother liquor as a high-purity IV solution for concentration and crystallization; concentrating the quaternary recovered mother liquor under vacuum, adding formamide solvent, cooling, crystallizing, and filtering to obtain quinary recovered powder; adding the quinary recovered powder to an ethanol-water solution, adding formamide solvent, dissolving at a higher temperature, cooling, crystallizing, and filtering to obtain ivermectin. This application utilizes a low-concentration ethanol-water solution to treat low-content recovered powder, altering the crystallization properties of ivermectin, achieving pre-crystallization separation of byproduct impurities, purifying the ivermectin mother liquor, and fully utilizing the waste mother liquor, thus saving costs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for purifying low-content ivermectin recovery powder. Background Technology

[0002] Ivermectin is a novel macrolide antibiotic anthelmintic with advantages such as high efficacy, broad spectrum, and low toxicity. It is currently widely used as an insecticide and acaricide for humans, animals, and plants. Its structural formula is as follows:

[0003]

[0004] Ivermectin is a sixteen-membered macrolide antibiotic that is readily soluble in methanol, ethanol, acetone, and ethyl acetate, almost insoluble in water, and slightly hygroscopic.

[0005] Ivermectin is a novel, broad-spectrum, highly effective, and low-toxicity antibiotic antiparasitic drug. It has good killing effects on both internal and external parasites, especially nematodes and arthropods, but it is ineffective against tapeworms, trematodes, and protozoa. The killing effect of macrolide antiparasitic drugs on nematodes and arthropods lies in increasing the release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the parasite and opening glutamate-controlled Cl ion channels, enhancing the permeability of nerve membranes to Cl, thereby blocking the transmission of nerve signals, ultimately causing nerve paralysis, and rendering muscle cells unable to contract, leading to the death of the parasite.

[0006] In existing technologies, ivermectin is produced using avermectin as the main raw material, toluene as the solvent, and triphenylphosphine rhodium chloride as the catalyst. The ivermectin is catalytically hydrogenated under high temperature and pressure to produce ivermectin (IV) (the main component is IVB1). The catalytic reaction is then removed, and the product is concentrated and dried to obtain crude ivermectin powder. This is then purified by cooling and crystallization using a specific ratio of ethanol, water, and formamide solvent to obtain refined ivermectin powder. During the preparation of ivermectin, an impurity, 2HIV, is generated, as shown in the following equation.

[0007]

[0008] The waste mother liquor generated during the production of ivermectin products undergoes deep concentration to recover organic solvents, simultaneously yielding a low-content ivermectin recovery powder with a content of only 30-50%. The newly generated primary recovery mother liquor is further concentrated to recover solvents, producing a secondary recovery powder. This secondary recovery powder has a lower effective component content and a higher impurity content. During cooling and crystallization, impurities and effective components precipitate simultaneously, making it impossible to refine through crystallization. Therefore, it is disposed of as hazardous waste. This practice results in product waste and high hazardous waste disposal costs. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a purification method for low-content ivermectin recovery powder. The present invention focuses on the process development of ivermectin recovery powder products with low content and high impurity content, extracting and refining ivermectin from the powder, thereby achieving the goals of improving yield, reducing hazardous waste, and reducing costs.

[0010] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0011] A method for purifying low-content ivermectin recovered powder includes the following steps:

[0012] Step S1: Dissolve the ivermectin secondary recovery powder in an ethanol aqueous solution, heat, stir at a constant temperature, cool, and filter to obtain the tertiary recovery powder;

[0013] Step S2: Add ethanol aqueous solution to the three-times recovered powder, heat until dissolved, cool, crystallize, filter to obtain four-times recovered powder and four-times recovered mother liquor, and use the four-times recovered mother liquor as a high-purity IV solution for concentration and crystallization.

[0014] Step S3: The mother liquor from the fourth recovery is heated and concentrated under vacuum, formamide solvent is added, the temperature is lowered, crystals are precipitated, and the mixture is filtered to obtain the fifth recovery powder, i.e., ivermectin crude powder.

[0015] Step S4: Add the five-times recovered powder to an ethanol-water solution, then add formamide solvent, heat to dissolve, cool, crystallize, and filter to obtain ivermectin.

[0016] A further improvement of the technical solution of the present invention is that the ivermectin secondary recovery powder is obtained by the second concentration and recovery of the waste mother liquor in the preparation process of ivermectin.

[0017] A further improvement of the technical solution of the present invention is that the volume fraction of the ethanol solution in step S1 is 10%, and the volume fraction of the ethanol solution in steps S2 and S4 is 90%.

[0018] A further improvement to the technical solution of the present invention is that: in step S1, the mass-to-volume ratio of the secondary recovery powder and the ethanol aqueous solution is 1:2-5 g / mL, the temperature is raised to 70℃~75℃, stirred for 4 hours, and then cooled to 15℃.

[0019] A further improvement to the technical solution of the present invention is that: in step S2, the mass-to-volume ratio of the three-times recovered powder and the ethanol aqueous solution is 1:1-3 g / mL, the temperature is raised to 70℃~75℃, and then lowered to 15℃.

[0020] A further improvement to the technical solution of the present invention is that: in step S3, the mother liquor recovered four times is heated and vacuum concentrated to 0.7 times the initial volume, the volume of formamide solvent added is 0.1-0.6 times the volume of the mother liquor recovered four times, and then cooled to 15°C.

[0021] A further improvement of the technical solution of the present invention is that: the mother liquor obtained after five recycling powders in step S3 can be deeply concentrated to recover the solvent, and the solid precipitate can be recycled by repeating steps S1-S3.

[0022] A further improvement of the technical solution of the present invention is that: in step S4, the weight-volume ratio of the five-times recovered powder and the ethanol aqueous solution is 1:2-3 g / mL, the weight-volume ratio of the five-times recovered powder and the formamide solvent is 1:0.1-0.3 g / mL, the temperature is raised to 70℃~75℃ to dissolve, and then the temperature is lowered to 15℃.

[0023] A further improvement of the technical solution of the present invention is that: the purity of ivermectin obtained in step S4 is ≥95%, the mother liquor obtained in step S4 is deeply concentrated to recover the solvent, and the solid precipitate is recycled by repeating steps S1-S4.

[0024] The technological advancements achieved by this invention due to the adoption of the above technical solutions are as follows:

[0025] This application presents a method for extracting ivermectin from low-content ivermectin mother liquor. The method is simple to operate and yields high-purity recovered ivermectin. It employs a novel approach, first crystallizing and separating impurities in the mother liquor, and then purifying and separating the mother liquor to obtain pure ivermectin. The method is novel, utilizing a low-concentration ethanol aqueous solution to treat the low-content recovered powder, thereby changing the crystallization properties of ivermectin and achieving the pre-crystallization and separation of by-product impurities. This purifies the ivermectin mother liquor and makes full use of the waste mother liquor, saving costs. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to embodiments:

[0027] The crystallization mother liquor generated during the production of ivermectin products is concentrated and recrystallized to obtain ivermectin primary recovery powder. The waste mother liquor generated is then deeply concentrated to recover the organic solvent, and at the same time, a low-content ivermectin secondary recovery powder is obtained. This recovery powder can be purified through a patented method.

[0028] Example 1

[0029] 1. Place 100g of ivermectin secondary recovery powder into a three-necked flask, add 200mL of 10% ethanol aqueous solution, turn on the stir and heat to 60-70℃, stir for 3-4 hours, cool to 15-20℃, filter to obtain tertiary recovery powder, with a weight yield of 95%. Concentrate the mother liquor to recover the ethanol from the solvent. The solid residue is mainly product impurities and should be disposed of as hazardous waste.

[0030] 2. Add 95g of the three-stage recovery powder to a three-necked flask, add 95mL of 90% ethanol aqueous solution, stir and heat to 70℃ to dissolve, then allow to cool naturally to 15℃ to crystallize. Filter to obtain 38g of the four-stage recovery powder, which will be disposed of as hazardous waste. The mother liquor from the four-stage recovery will be used as a high-purity IV solution for concentration and crystallization.

[0031] 3. Take the mother liquor from the fourth recovery (containing approximately 57 grams of product) and add it to a rotary evaporator. Heat and concentrate under vacuum to 0.7 times the original volume. Pour into a three-necked flask, add 6 mL of formamide solvent, stir and heat to 65°C, then allow to cool naturally to 15°C. Filter to obtain 20 grams of the fifth recovery powder. The yield of the fifth recovery powder is 35%, and the product quality is IVB1% ≥ 85%. The mother liquor can be further concentrated to recover the solvent, and the solid precipitate can be repeatedly processed in steps 1-3.

[0032] 4. Take 20g of the fifth-stage recovery powder and add it to a three-necked flask. Add 40mL of 10% ethanol aqueous solution and 90% ethanol aqueous solution respectively, and then add 2mL of formamide solvent. Heat to 70℃ to dissolve, and then cool to 15℃ to obtain 16g of the sixth-stage recovery powder. The yield is 80%, the total yield is 16%, and the product quality is ivermectin IVB1% ≥ 95%. The mother liquor is deeply concentrated to recover the solvent, and the solid precipitate is recycled in steps 1-4.

[0033] Example 2

[0034] 1. Place 100g of ivermectin secondary recovery powder into a three-necked flask, add 300mL of 10% ethanol aqueous solution, turn on the stir and heat to 60-70℃, stir for 3-4 hours, cool to 15-20℃, filter to obtain tertiary recovery powder, with a weight yield of 93%. Concentrate the mother liquor to recover ethanol, and dispose of the solid residue as hazardous waste.

[0035] 2. Add 93g of the three-stage recovery powder to a three-necked flask, add 200mL of 90% ethanol aqueous solution, stir and heat to 70℃ to dissolve, then allow to cool naturally to 15℃, filter to obtain 33g of the four-stage recovery powder, which will be disposed of as hazardous waste. The mother liquor from the four-stage recovery will be used as a high-purity IV solution for concentration and crystallization.

[0036] 3. Take the mother liquor from the fourth recovery (containing approximately 60 grams of product) and add it to a rotary evaporator. Heat and concentrate under vacuum to 0.7 times the original volume. Pour into a three-necked flask, add 12 mL of formamide solvent, stir and heat to 65°C, then allow to cool naturally to 15°C. Filter to obtain 21 grams of the fifth recovery powder. The yield of the fifth recovery powder is 35%, and the product quality is IVB1% ≥ 85%. The mother liquor can be further concentrated to recover the solvent, and the solid precipitate can be repeatedly processed in steps 1-3.

[0037] 4. 21 grams of the fifth-stage recovered powder were added to a three-necked flask, and 50 mL of 10% ethanol aqueous solution and 90% ethanol aqueous solution were added respectively. Then, 4 mL of formamide solvent was added and the temperature was raised to 70°C to dissolve the powder. The temperature was then lowered to 15°C to obtain 18 grams of the sixth-stage recovered powder, with a yield of 86% and a total yield of 18%. The product quality was IVB1% ≥ 95%. The mother liquor was deeply concentrated to recover the solvent, and the solid precipitate was recycled in steps 1-4.

[0038] Example 3

[0039] 1. Take 100g of ivermectin secondary recovery powder and put it into a three-necked flask. Add 500mL of solvent A, turn on the stir and heat to 60-70℃. Stir for 3-4 hours, cool to 15-20℃, and filter to obtain tertiary recovery powder with a weight yield of 92%. Concentrate the mother liquor to recover solvent A, and dispose of the solid residue as hazardous waste.

[0040] 2. Add 92g of the three-stage recovery powder to a three-necked flask, add 285mL of 90% ethanol aqueous solution, stir and heat to 70℃ to dissolve, then allow to cool naturally to 15℃, filter to obtain 30g of the four-stage recovery powder, which will be disposed of as hazardous waste. The mother liquor from the four-stage recovery will be used as a high-purity IV solution for concentration and crystallization.

[0041] 3. Take the mother liquor from the fourth recovery (containing approximately 62 grams of product) and add it to a rotary evaporator. Heat and concentrate under vacuum to 0.7 times the original volume. Pour into a three-necked flask, add 18 mL of formamide solvent, stir and heat to 65°C, then allow to cool naturally to 15°C. Filter to obtain 21 grams of the fifth recovery powder. The yield of the fifth recovery powder is 34%, and the product quality is IVB1% ≥ 85%. The mother liquor can be further concentrated to recover the solvent, and the solid precipitate can be repeatedly processed in 1-3 steps.

[0042] 4. 21 grams of the five-stage recovery powder were added to a three-necked flask, and 60 mL of 10% ethanol aqueous solution and 90% ethanol aqueous solution were added respectively. Then, 6 mL of formamide solvent was added and the temperature was raised to 70°C to dissolve the powder. The temperature was then lowered to 15°C to obtain 18 grams of the six-stage recovery powder, with a yield of 86% and a total yield of 18%. The product quality was IVB1% ≥ 95%. The mother liquor was deeply concentrated to recover the solvent, and the solid precipitate was recycled in steps 1-4.

[0043] Liquid chromatography analysis was performed on the three-stage, five-stage, and six-stage recovered powders obtained in the examples. The product quality inspection results are as follows:

[0044]

Claims

1. A method for purifying low-content ivermectin recovery powder, characterized in that: Includes the following steps: Step S1: Dissolve the ivermectin secondary recovery powder in an ethanol aqueous solution, heat, stir at a constant temperature, cool, and filter to obtain the tertiary recovery powder; The ivermectin secondary recovery powder is obtained by the second concentration and recovery of the waste mother liquor during the ivermectin preparation process; Step S2: Add ethanol aqueous solution to the three-times recovered powder, heat and stir until dissolved, cool down, crystallize, filter to obtain four-times recovered powder and four-times recovered mother liquor, and use the four-times recovered mother liquor as a high-purity IV solution for concentration and crystallization. IV is ivermectin; Step S3: The mother liquor from the fourth recovery is heated and concentrated under vacuum, formamide solvent is added, the temperature is lowered, crystals are precipitated, and the mixture is filtered to obtain the fifth recovery powder, i.e., ivermectin crude powder. Step S4: Add the five-times recovered powder to an ethanol-water solution, then add formamide solvent, heat to dissolve, cool, crystallize, and filter to obtain ivermectin; The volume fraction of the ethanol solution in step S1 is 10%, and the volume fraction of the ethanol solution in steps S2 and S4 is 90%.

2. The purification method for low-content ivermectin recovery powder according to claim 1, characterized in that: In step S1, the mass-to-volume ratio of the secondary recovery powder and the ethanol aqueous solution is 1:2-5 g / mL. The temperature is raised to 70℃~75℃, stirred for 4 hours, and then cooled to 15℃.

3. The purification method for low-content ivermectin recovery powder according to claim 1, characterized in that: In step S2, the mass-to-volume ratio of the three recovered powders and the ethanol-water solution is 1:1-3 g / mL, the temperature is raised to 70℃~75℃, and then lowered to 15℃.

4. The purification method for low-content ivermectin recovery powder according to claim 1, characterized in that: In step S3, the mother liquor recovered from the four times is heated and vacuum concentrated to 0.7 times its initial volume. The volume-to-mass ratio of the added formamide solvent to the recovered powder from the four times is 0.1-0.6 mL / mg. The temperature is then lowered to 15°C.

5. The purification method for low-content ivermectin recovery powder according to claim 1, characterized in that: The mother liquor obtained after five rounds of recycled powder in step S3 can be further concentrated to recover the solvent, and the solid precipitates can be recycled by repeating steps S1-S3.

6. The purification method for low-content ivermectin recovery powder according to claim 1, characterized in that: In step S4, the weight-to-volume ratio of the five-times recovered powder to the ethanol-water solution is 1:2-3 g / mL, and the weight-to-volume ratio of the five-times recovered powder to the formamide solvent is 1:0.1-0.3 g / mL. The mixture is heated to 70℃~75℃ to dissolve and then cooled to 15℃.

7. The purification method for low-content ivermectin recovery powder according to claim 1, characterized in that: The purity of ivermectin obtained in step S4 is ≥95%. The mother liquor obtained in step S4 is concentrated to recover the solvent, and the solid precipitate is recycled by repeating steps S1-S4.

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