A purification method for medical-grade polyethylene glycol-polycaprolactone block copolymer

Abstract

This invention discloses a purification method for medical-grade polyethylene glycol-polycaprolactone block copolymer, belonging to the field of medical polymer material synthesis technology. The purification method includes the following steps: supercritical carbon dioxide extraction of crude polyethylene glycol-polycaprolactone block copolymer for 30-120 min; dissolving the extracted product in solvent one, filtering with alkaline quartz sand, concentrating the filtrate, precipitating with solvent two, and drying the precipitate to obtain the medical-grade polyethylene glycol-polycaprolactone block copolymer. The purification method for medical-grade polyethylene glycol-polycaprolactone block copolymer provided by this invention uses supercritical extraction combined with alkaline quartz sand filtration, which is simple, quick, and has good tin removal effect, reducing the tin content to below 20 ppm. Furthermore, the molecular weight does not change significantly before and after purification, and the product loss during purification is less than 5%. The amount of solvent used in the purification process is also relatively small.

Description

Technical Field

[0001] This invention relates to the field of medical polymer material synthesis technology, and in particular to a purification method for medical polyethylene glycol-polycaprolactone block copolymer. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Polyethylene glycol-polycaprolactone (PEG-PCL) block copolymers are commonly used in drug delivery, biomaterials, and tissue engineering. Their synthesis typically involves organotin compounds (such as stannous octoate catalysts or other tin catalysts). If the tin content in such materials exceeds the limit, the excessive tin content may have the following effects: (1) Cytotoxicity: adversely affects cell survival, proliferation, and differentiation; (2) Immunosuppression: inhibits the normal function of the immune system and increases the risk of infection; (3) Neurotoxicity: organotin may interfere with the normal function of the nervous system; (4) Reproductive toxicity: high doses of tin compounds may lead to decreased fertility; during the use or disposal of such materials, tin may enter water bodies, causing water pollution and toxic effects on aquatic organisms; (5) Inflammatory response: toxic residues in the materials may trigger local or systemic inflammation; (6) Long-term toxicity accumulation: tin compounds in the human body may accumulate through metabolism, causing chronic health problems.

[0004] To reduce the risk of excessive tin content, traditional methods for preparing polyethylene glycol-polycaprolactone (PEG-PCL) block copolymers often employ the following approaches: First, optimizing the synthesis process: selecting more environmentally friendly catalysts (such as organic acid catalysts) or improving reaction conditions to reduce the amount of tin compounds used. However, this method often results in poor catalytic performance, leading to low yields and wide molecular weight distributions of the obtained PEG-PCL block copolymers. Second, rigorous purification: removing catalyst residues through multiple steps and repeated purification (such as dialysis, recrystallization, and acid washing). This comes at the cost of wasted solvents and product loss, ultimately increasing production costs. Furthermore, repeated washing may cause molecular weight degradation, making it difficult to ensure consistency in molecular weight before and after treatment.

[0005] Patent CN105315444B discloses a purification method for injectable polyethylene glycol monomethyl ether-polylactic acid amphiphilic block copolymer. It uses a strong acidic cation exchange resin combined with microporous membrane filtration to remove tin, which can obtain a purified product with a tin content of less than 10 ppm. However, this method requires a large amount of ion exchange material, and the regeneration of the ion exchange material must also be considered. This method generates a large amount of acid and alkaline waste liquid, resulting in high treatment costs.

[0006] Therefore, how to provide a high-efficiency polyethylene glycol-polycaprolactone block copolymer with good tin removal effect, high yield and no significant degradation of molecular chains is an urgent problem to be solved. Summary of the Invention

[0007] In view of this, the present invention provides a purification method for medical polyethylene glycol-polycaprolactone block copolymer. The purification method used in the present invention can reduce the tin content to below 20 ppm, and the molecular weight changes before and after purification are not significant, the molecular weight distribution is narrow (PDI<1.4), and the loss of purified product is less than 5%.

[0008] In a first aspect, the present invention provides a method for purifying medical-grade polyethylene glycol-polycaprolactone block copolymer, comprising the following steps:

[0009] The crude polyethylene glycol-polycaprolactone block copolymer was subjected to supercritical carbon dioxide extraction for 30–120 min. The extracted product was then dissolved in solvent one, filtered through alkaline quartz sand, concentrated, precipitated through solvent two, and dried to obtain medical-grade polyethylene glycol-polycaprolactone block copolymer.

[0010] Secondly, the present invention provides a medical polyethylene glycol-polycaprolactone block copolymer obtained by the above purification method.

[0011] Thirdly, the present invention provides polyethylene glycol-polycaprolactone block copolymer microspheres, which are prepared from the above-mentioned medical polyethylene glycol-polycaprolactone block copolymer.

[0012] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0013] The purification method for medical polyethylene glycol-polycaprolactone block copolymer provided by this invention adopts supercritical extraction combined with alkaline quartz sand filtration. This method is simple, short in time, and has a good tin removal effect, reducing the tin content to below 20 ppm. Moreover, the molecular weight does not change significantly before and after purification, and the product loss during the purification process is less than 5%. The amount of solvent used in the purification process is small, and the tin salt catalyst obtained by supercritical extraction can be reused. Attached Figure Description

[0014] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0015] Figure 1 This is the 1H NMR spectrum of the methoxy polyethylene glycol-polycaprolactone block copolymer of Example 1 of the present invention;

[0016] Figure 2 This is the infrared spectrum of the methoxy polyethylene glycol-polycaprolactone block copolymer of Example 1 of the present invention;

[0017] Figure 3 This is a scanning electron microscope image of the methoxy polyethylene glycol-polycaprolactone block copolymer microspheres of Example 1 of the present invention. Detailed Implementation

[0018] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0019] This invention provides a method for purifying medical-grade polyethylene glycol-polycaprolactone block copolymer, comprising the following steps:

[0020] The crude polyethylene glycol-polycaprolactone block copolymer was subjected to supercritical carbon dioxide extraction for 30–120 min. The extracted product was then dissolved in solvent one, filtered through alkaline quartz sand, concentrated, precipitated through solvent two, and dried to obtain medical-grade polyethylene glycol-polycaprolactone block copolymer.

[0021] This invention first employs supercritical carbon dioxide extraction to treat crude polyethylene glycol-polycaprolactone block copolymer. Supercritical extraction has been preliminarily applied in the extraction of active components from traditional Chinese medicine and the removal of heavy metals; however, when used for heavy metal removal, it usually requires the addition of suitable complexing agents, modifiers, and special matrices to improve the removal efficiency, generally referred to as supercritical coordination extraction. However, this invention discovers that even without the addition of complexing agents, modifiers, or special matrices, it can still achieve good tin removal results, reducing processing difficulty and costs. Using carbon dioxide as the supercritical fluid offers advantages such as fast extraction speed, high extraction rate, low extraction temperature, good biocompatibility, and non-toxicity and pollution-free operation. The supercritical carbon dioxide extraction time affects the tin removal efficiency; too short an extraction time will not achieve good tin removal, while too long an extraction time has little impact on improving the tin removal efficiency.

[0022] In this invention, the temperature of the supercritical carbon dioxide extraction is 30–70°C, more preferably 30–50°C; and the extraction pressure is 10–30 MPa.

[0023] In this invention, the ratio of crude polyethylene glycol-polycaprolactone block copolymer to solvent one is 1 g:(3-7) mL; the ratio of crude polyethylene glycol-polycaprolactone block copolymer to solvent two is 1 g:(8-15) mL. The filtrate is concentrated until the volume is reduced by 65-85%. This invention does not impose special limitations on the concentration method; most of the solvent can be removed by vacuum distillation, rotary evaporation, evaporation, heating, etc.

[0024] In this invention, the alkaline quartz sand is a mixture of an alkaline substance and quartz sand, with a mass ratio of alkaline substance to quartz sand of (1-2):(8-9). This invention uses alkaline quartz sand to filter the extracted and dissolved products. The alkaline quartz sand can remove residual organotin impurities from the product mixture, reducing them from a stoichiometric level to ~20 ppm. Further, the alkaline substance is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and calcium carbonate. This invention does not impose special limitations on the alkaline quartz sand filtration process; commonly used alkaline quartz sand filtration methods in the art can be employed.

[0025] In this invention, the preparation method of the crude polyethylene glycol-polycaprolactone block copolymer is as follows: dried polyethylene glycol, caprolactone and tin salt are reacted at a constant temperature under inert gas protection, then dissolved with solvent three, precipitated with solvent four and vacuum dried to obtain the crude copolymer.

[0026] In this invention, solvent one and solvent three are each independently selected from one or more of dimethyl sulfoxide, chloroform, xylene, n-hexane, acetonitrile, dimethylformamide, ethyl acetate, dichloromethane, butanone, and ethanol; solvent one and solvent three must have good solubility for the PEG-PCL block copolymer. To facilitate solvent removal, dichloromethane is more preferably used in this invention. Solvent two and solvent four are each independently selected from one or more of diethyl ether, n-octane, isohexane, toluene, or petroleum ether. These solvents are poor solvents for the PEG-PCL block copolymer, making it easier to collect and dry after precipitation.

[0027] This invention does not impose any special restrictions on the drying methods for polyethylene glycol and caprolactone, as long as the moisture can be completely removed to avoid adverse effects on the reaction. This invention does not impose any special restrictions on the type of polyethylene glycol, and it can be selected from various types of polyethylene glycol such as methoxy polyethylene glycol (mPEG), branched polyethylene glycol, multi-arm polyethylene glycol, and cross-linked polyethylene glycol; this invention also does not impose any special restrictions on its molecular weight, which can be 100 to 10000; the polyethylene glycol of this invention is preferably one or more of mPEG100, mPEG200, mPEG300, mPEG400, mPEG600, mPEG1000, mPEG2000, mPEG4000, mPEG6000, mPEG8000, mPEG10000, PEG100, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000, PEG8000, or PEG10000.

[0028] In this invention, the mass ratio of polyethylene glycol to caprolactone is (20-80):(20-80), for example, 30:70, 40:60, 70:30, etc. The mass fraction of the tin salt is 0.5-2 wt%, which refers to the percentage of the mass of the tin salt to the total mass of the tin salt, polyethylene glycol, and caprolactone. The tin salt is selected from one or more of tin methanesulfonate, dioctyltin, triphenyltin, triethyltin, tetramethyltin, dibutyltin dilaurate, or stannous octoate; in one or more embodiments of this invention, the tin salt is selected from stannous octoate.

[0029] In this invention, the isothermal reaction temperature is 90–120°C, more preferably 100–110°C; the reaction time is 10–20 h, more preferably 10–15 h; the inert gas is one or more of nitrogen or rare gases, preferably nitrogen. Before adding the tin salt, an inert gas must be introduced to remove oxygen and residual moisture from the reaction system.

[0030] This invention provides a medical-grade polyethylene glycol-polycaprolactone block copolymer obtained by the above purification method. The tin content of the medical-grade polyethylene glycol-polycaprolactone block copolymer obtained by the above purification method of this invention is below 20 ppm, which meets the performance requirements of medical filler materials.

[0031] This invention also provides polyethylene glycol-polycaprolactone block copolymer microspheres, which are prepared from the above-mentioned medical polyethylene glycol-polycaprolactone block copolymer. The preparation method can be solvent evaporation, double emulsification, spray drying, supercritical dispersion, melt method, or ion gel method, etc. The obtained polyethylene glycol-polycaprolactone block copolymer microspheres can be used to prepare dermal filler injections.

[0032] The technical solution of the present invention will be further described below with reference to specific embodiments. The present invention does not have any special restrictions on the source of reagents used in the following embodiments; commercially available products well known to those skilled in the art can be used. In the following embodiments, room temperature refers to 25±3℃.

[0033] Example 1

[0034] This embodiment provides a method for preparing and purifying a methoxy polyethylene glycol-polycaprolactone block copolymer and a method for preparing copolymer microspheres.

[0035] (1) Raw material drying: mPEG4000 was placed in a vacuum drying oven and dried at 50°C for 7 hours to remove moisture from the raw material. An appropriate amount of calcium hydride was added to the caprolactone monomer, and the mixture was sealed and left to stand in a desiccator for 48 hours to thoroughly dry the monomer.

[0036] (2) Preparation of crude methoxy polyethylene glycol-polycaprolactone block copolymer: 40g of pretreated mPEG4000 and 40g of caprolactone monomer were added to a dry reactor. The reactor was sealed, heated to 100℃, and purged under nitrogen protection for 1 hour to further remove residual moisture and oxygen. After cooling to room temperature, 0.81g of stannous octoate was quickly added as a catalyst, and the temperature was raised again to 110℃. The reaction was maintained at a constant temperature with stirring for 12 hours. After the reaction was completed, the reaction product was cooled to room temperature and dissolved thoroughly in 200mL of dichloromethane to obtain a homogeneous solution. The solution was slowly poured into 450mL of petroleum ether and stirred thoroughly to precipitate the polymer. The precipitated polymer was collected, filtered under vacuum, and the solid was transferred to a vacuum drying oven and dried to constant weight at 50℃ to obtain 78g of crude product, with a yield of 96.5%.

[0037] (3) Purification of crude methoxy polyethylene glycol-polycaprolactone block copolymer: Take 40g of the crude product from step (2) and fill it into the extraction tank of a supercritical extraction device. Set the supercritical carbon dioxide extraction temperature to 40℃ and the extraction pressure to 15MPa. After the temperature reaches the set value, open the CO2 cylinder and turn on the run button on the CO2 high-pressure pump to start pressurization. Liquid CO2 enters the extraction tank through the high-pressure pump. After reaching the set pressure, stop the high-pressure pump and extract for 60 minutes. Release the pressure and collect the extracted organotin salt. Add 200mL of dichloromethane to the purified block copolymer obtained in the extraction tank and stir until completely dissolved. Filter with 100g of alkaline quartz sand (the mass ratio of potassium carbonate to quartz sand is 2:8) and collect the filtrate. Concentrate the filtrate under reduced pressure using a rotary evaporator. Add 450mL of petroleum ether to about 50mL of the concentrate for reprecipitation and collect the precipitate. Finally, the precipitate was placed in a vacuum drying oven and dried at 50°C to constant weight, yielding 38.96g of purified product with a yield of 97.38%.

[0038] The purified product was subjected to 1H NMR spectroscopy, such as... Figure 1 As shown, this demonstrates the successful synthesis of the PEG-PCL block copolymer. Figure 2 The infrared spectrum of the refined product obtained in this embodiment is shown at 1380 cm⁻¹. -1 The left and right peaks are the bending vibration peaks of the hydroxyl group (-OH); 1188 cm⁻¹ -1 The left and right sides are absorption peaks of the -COC- stretching vibration; 1721 cm⁻¹ -1 The left and right peaks are absorption peaks of the carbonyl C=O stretching vibration; 2945 and 2858 cm⁻¹ -1 The left and right sides are the stretching vibration peaks of CH; 3431 cm⁻¹ -1 The broad peaks appearing on the left and right are stretching vibration peaks of -OH, indicating that the polymer contains hydroxyl terminal groups.

[0039] (4) Preparation of methoxy polyethylene glycol-polycaprolactone block copolymer microspheres: Weigh 10g of the refined product obtained in step (3) and place it in a clean beaker. Add 20mL of dichloromethane (DCM) as a solvent. Stir with a magnetic stirrer at 500rpm until completely dissolved to form a uniform, colorless, and transparent organic phase solution. If any solid remains undissolved, extend the stirring time appropriately to ensure complete dissolution. In another clean beaker, weigh 1g of polyvinyl alcohol (PVA), add 50mL of pure water, heat and stir at 80℃ until completely dissolved to prepare a 2% PVA aqueous solution. After the solution cools to room temperature, set aside. At room temperature, slowly add the prepared organic phase solution to the cooled PVA aqueous solution using a dropper or syringe. During this process, the aqueous phase needs to be strongly stirred at a speed of 600rpm for approximately 5 minutes. After the addition is complete, continue stirring for 15 minutes to initially form an emulsion. Subsequently, the mixture was transferred to an ultrasonic emulsifier and emulsified at 300W using intermittent ultrasonic treatment (5 seconds working time, 3 seconds interval) for 2 minutes (ultrasonic treatment significantly improves emulsion stability and controls microsphere particle size distribution). The ultrasonically emulsified emulsion was transferred to an open beaker and placed on a magnetic stirrer at 400 rpm to evaporate the organic solvent (DCM) at room temperature, resulting in a stable microsphere suspension. The obtained microsphere suspension was poured into centrifuge tubes and centrifuged at 5000 rpm for 10 minutes. After centrifugation, the supernatant was discarded, and the precipitated microspheres were retained, then washed and dried to obtain the packing microspheres. The results showed that: Figure 3 As shown, the average diameter of the microspheres prepared by this method is approximately 36.5 μm, and all other indicators meet industry standards.

[0040] Example 2

[0041] This embodiment provides a method for preparing and purifying a methoxy-polyethylene glycol-polycaprolactone block copolymer and a method for preparing copolymer microspheres.

[0042] (1) Raw material drying: mPEG8000 was placed in a vacuum drying oven and dried at 50°C for 7 hours to remove moisture from the raw material. An appropriate amount of calcium hydride was added to the caprolactone monomer, and the mixture was sealed and left to stand in a desiccator for 48 hours to thoroughly dry the monomer.

[0043] (2) Preparation of crude methoxy polyethylene glycol-polycaprolactone block copolymer: 60g of pretreated mPEG8000 and 40g of caprolactone monomer were added to a dry reactor. The reactor was sealed, heated to 100℃, and purged under nitrogen protection for 1 hour to further remove residual moisture and oxygen. After cooling to room temperature, 1.52g of stannous octoate was quickly added as a catalyst, and the temperature was raised again to 110℃. The reaction was maintained at a constant temperature with stirring for 12 hours. After the reaction, the reaction product was cooled to room temperature and dissolved thoroughly in 300mL of dichloromethane to obtain a homogeneous solution. The solution was slowly poured into 600mL of petroleum ether and stirred thoroughly to precipitate the polymer. The precipitated polymer was collected, filtered under vacuum, and the solid was transferred to a vacuum drying oven and dried at 50℃ to constant weight, yielding 98.4g of crude product with a yield of 96.9%.

[0044] (3) Purification of crude methoxy polyethylene glycol-polycaprolactone block copolymer: Take 40g of the crude product from step (2) and fill it into the extraction tank of a supercritical extraction device. Set the supercritical carbon dioxide extraction temperature to 50℃ and the extraction pressure to 20MPa. After the temperature reaches the set value, open the CO2 cylinder and turn on the run button on the CO2 high-pressure pump to start pressurization. Liquid CO2 enters the extraction tank through the high-pressure pump. After reaching the set pressure, stop the high-pressure pump and extract for 40 minutes. Release the pressure and collect the extracted organotin salt. Add 200mL of dichloromethane to the purified block copolymer obtained in the extraction tank and stir until completely dissolved. Filter with 100g of alkaline quartz sand (the mass ratio of sodium carbonate to quartz sand is 2:8) and collect the filtrate. Concentrate the filtrate under reduced pressure using a rotary evaporator to remove the dichloromethane solvent. Add 450mL of petroleum ether to 50mL of the concentrate for reprecipitation and collect the precipitate. Finally, the precipitate was placed in a vacuum drying oven and dried at 50°C to constant weight, yielding 38.60g of refined product with a yield of 96.5%.

[0045] (4) Preparation of methoxy polyethylene glycol-polycaprolactone block copolymer microspheres: Weigh 15g of the refined product obtained in step (3) and place it in a clean beaker. Add 30mL of dichloromethane (DCM) as a solvent. Stir with a magnetic stirrer at 600rpm until completely dissolved to form a uniform, colorless, and transparent organic phase solution. If any solid remains undissolved, extend the stirring time appropriately to ensure complete dissolution. In another clean beaker, weigh 1.5g of polyvinyl alcohol (PVA), add 50mL of pure water, heat and stir at 80℃ until completely dissolved to prepare a 3% PVA aqueous solution. After the solution cools to room temperature, set aside. At room temperature, slowly add the prepared organic phase solution to the cooled PVA aqueous solution using a dropper or syringe. During this process, the aqueous phase needs to be strongly stirred at 800rpm for approximately 5 minutes. After the addition is complete, continue stirring for 15 minutes to initially form an emulsion. The mixture was then transferred to an ultrasonic emulsifier and emulsified at 300W using intermittent ultrasonic treatment (10-second working time, 3-second interval) for 2 minutes (ultrasonic treatment significantly improves emulsion stability and controls microsphere particle size distribution). The ultrasonically emulsified emulsion was transferred to an open beaker and placed on a magnetic stirrer at 500 rpm to evaporate the organic solvent (DCM) at room temperature, resulting in a stable microsphere suspension. The obtained microsphere suspension was poured into centrifuge tubes and centrifuged at 5000 rpm for 10 minutes. After centrifugation, the supernatant was discarded, and the precipitated microspheres were retained, then washed and dried to obtain the filler microspheres. The average diameter of the microspheres prepared by this method was approximately 30.5 μm, and all other indicators met industry standards.

[0046] Example 3

[0047] This embodiment provides a method for preparing and purifying a methoxy polyethylene glycol-polycaprolactone block copolymer and a method for preparing copolymer microspheres.

[0048] (1) Raw material drying: mPEG10000 was placed in a vacuum drying oven and dried at 50°C for 7 hours to remove moisture from the raw material. An appropriate amount of calcium hydride was added to the caprolactone monomer, and after sealing, it was placed in a desiccator for 48 hours to thoroughly dry the monomer.

[0049] (2) Preparation of crude methoxy polyethylene glycol-polycaprolactone block copolymer: 30g of pretreated mPEG10000 and 70g of caprolactone monomer were added to a dry reactor. The reactor was sealed, heated to 100℃, and purged under nitrogen protection for 1 hour to further remove residual moisture and oxygen. After cooling to room temperature, 1.01g of stannous octoate was quickly added as a catalyst, and the temperature was raised again to 110℃. The reaction was maintained at a constant temperature with stirring for 12 hours. After the reaction, the reaction product was cooled to room temperature and dissolved thoroughly in 200mL of dichloromethane to obtain a homogeneous solution. The solution was slowly poured into 450mL of petroleum ether and stirred thoroughly to precipitate the polymer. The precipitated polymer was collected, filtered under vacuum, and the solid was transferred to a vacuum drying oven and dried at 50℃ to constant weight to obtain 98.1g of crude product, with a yield of 97.1%.

[0050] (3) Purification of crude methoxy polyethylene glycol-polycaprolactone block copolymer: Take 40g of the crude product from step (2) and fill it into the extraction tank of a supercritical extraction device. Set the supercritical carbon dioxide extraction temperature to 40℃ and the extraction pressure to 10MPa. After the temperature reaches the set value, open the CO2 cylinder and turn on the run button on the CO2 high-pressure pump to start pressurization. Liquid CO2 enters the extraction tank through the high-pressure pump. After reaching the set pressure, stop the high-pressure pump and extract for 90 minutes. Release the pressure and collect the extracted organotin salt. Add 200mL of dichloromethane to the purified block copolymer obtained in the extraction tank and stir until completely dissolved. Filter with 100g of alkaline quartz sand (the mass ratio of potassium carbonate to quartz sand is 1:9) and collect the filtrate. Concentrate the filtrate under reduced pressure using a rotary evaporator to remove the dichloromethane solvent. Add 450mL of petroleum ether to 50mL of the concentrate for reprecipitation and collect the precipitate. Finally, the precipitate was placed in a vacuum drying oven and dried at 50°C to constant weight, yielding 39.17g of purified product with a yield of 97.93%.

[0051] (4) Preparation of methoxy polyethylene glycol-polycaprolactone block copolymer microspheres: Weigh 10g of the refined product obtained in step (3) and place it in a clean beaker. Add 20mL of dichloromethane (DCM) as a solvent. Stir with a magnetic stirrer at 800rpm until completely dissolved to form a uniform, colorless, and transparent organic phase solution. If any solid remains undissolved, extend the stirring time appropriately to ensure complete dissolution. In another clean beaker, weigh 2.5g of polyvinyl alcohol (PVA), add 50mL of pure water, heat and stir at 80℃ until completely dissolved to prepare a 5% PVA aqueous solution. After the solution cools to room temperature, set aside. At room temperature, slowly add the prepared organic phase solution to the cooled PVA aqueous solution using a dropper or syringe. During this process, the aqueous phase needs to be strongly stirred at a speed of 600rpm for approximately 5 minutes. After the addition is complete, continue stirring for 15 minutes to initially form an emulsion. The mixture was then transferred to an ultrasonic emulsifier and emulsified at 300W using intermittent ultrasonic treatment (8 seconds of operation followed by 2 seconds of rest) for 2 minutes (ultrasonic treatment significantly improves emulsion stability and controls microsphere particle size distribution). The ultrasonically emulsified emulsion was transferred to an open beaker and placed on a magnetic stirrer at 400 rpm to evaporate the organic solvent (DCM) at room temperature, resulting in a stable microsphere suspension. The microsphere suspension was then poured into centrifuge tubes and centrifuged at 5000 rpm for 10 minutes. After centrifugation, the supernatant was discarded, and the precipitated microspheres were retained, washed, and dried to obtain the filler microspheres. The average diameter of the microspheres prepared by this method was approximately 46.5 μm, and all other indicators met industry standards.

[0052] Comparative Example 1

[0053] The difference between this comparative example and Example 1 is that the supercritical extraction time in step (3) of this comparative example is 10 min.

[0054] Comparative Example 2

[0055] The difference between this comparative example and Example 1 is that in step (3) of this comparative example, the alkaline quartz sand filtration step is not performed. Instead, the product after supercritical extraction is stirred until completely dissolved, and then concentrated and precipitated.

[0056] Comparative Example 3

[0057] The difference between this comparative example and Example 1 is that in step (3) of this comparative example, the product after supercritical extraction is filtered only with quartz sand, without adding potassium carbonate.

[0058] Comparative Example 4

[0059] The difference between this comparative example and Example 1 is that, in step (3) of this comparative example, supercritical extraction is not used. Instead, the crude product is stirred until completely dissolved, then filtered with alkaline quartz sand, concentrated, and precipitated. The specific steps of step (3) of this comparative example are as follows:

[0060] Take 40g of the crude product from step (2), add 200mL of dichloromethane, stir until completely dissolved, filter with 100g of alkaline quartz sand (potassium carbonate to quartz sand mass ratio of 2:8), and collect the filtrate. Concentrate the filtrate under reduced pressure using a rotary evaporator, add 450mL of petroleum ether to about 50mL of the concentrate for reprecipitation, and collect the precipitate. Finally, place the precipitate in a vacuum drying oven and dry it at 50℃ to constant weight to obtain 39.23g of purified product, with a yield of 98.08%.

[0061] Comparative Example 5

[0062] The difference between this comparative example and Example 1 is that step (3) of this comparative example is as follows:

[0063] Take 40g of the crude product from step (2), add 200mL of dichloromethane, stir until completely dissolved, add 10mL of 1.0M hydrochloric acid for acidification to convert the organotin to inorganic tin, wash repeatedly three times with 150mL*3 of deionized water, separate the layers, let stand, and collect the dichloromethane phase. Concentrate the collected solution under reduced pressure using a rotary evaporator, add 450mL of petroleum ether to about 50mL of the concentrate for reprecipitation, and collect the precipitate. Finally, place the precipitate in a vacuum drying oven and dry at 50℃ to constant weight to obtain 29.43g of purified product, with a yield of 73.58%.

[0064] Test case

[0065] The tin content of the crude and refined products of the examples and comparative examples was determined by inductively coupled plasma mass spectrometry (ICP-MS); the weight-average molecular weight (Mw) and molecular weight distribution (PDI) of the crude and refined products of the examples and comparative examples were determined by gel permeation chromatography (GPC). The results are shown in Table 1.

[0066] Table 1. Test results of crude and refined products from the examples and comparative examples.

[0067]

[0068] The test results from the examples and comparative examples show that the purification method of the present invention can efficiently remove tin content from the crude product. Shortening the supercritical extraction time, not using alkaline quartz sand filtration after supercritical extraction, using ordinary quartz sand filtration after supercritical extraction, or using only alkaline quartz sand filtration without supercritical treatment all fail to reduce the tin content to below 20 ppm. Acidification treatment, on the other hand, leads to product degradation and a decrease in the yield after purification.

[0069] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for purifying medical-grade polyethylene glycol-polycaprolactone block copolymer, characterized in that, Includes the following steps: The crude polyethylene glycol-polycaprolactone block copolymer was subjected to supercritical carbon dioxide extraction for 30-120 min. The extracted product was then dissolved in solvent one, filtered through alkaline quartz sand, concentrated, precipitated in solvent two, and dried to obtain medical-grade polyethylene glycol-polycaprolactone block copolymer. The tin content of the obtained medical-grade polyethylene glycol-polycaprolactone block copolymer was below 20 ppm.

2. The purification method according to claim 1, characterized in that, The supercritical carbon dioxide extraction temperature is 30~70 ℃, and the extraction pressure is 10~30 MPa.

3. The purification method as described in claim 1, characterized in that, The ratio of crude polyethylene glycol-polycaprolactone block copolymer to solvent one is 1 g : (3~7) mL; the ratio of crude polyethylene glycol-polycaprolactone block copolymer to solvent two is 1 g : (8~15) mL; concentrate the filtrate until the volume is reduced by 65~85%.

4. The purification method according to claim 1, characterized in that, The alkaline quartz sand is a mixture of alkaline substances and quartz sand, with a mass ratio of alkaline substances to quartz sand of (1~2): (8~9); the alkaline substances are selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and calcium carbonate.

5. The purification method according to claim 1, characterized in that, The preparation method of the crude polyethylene glycol-polycaprolactone block copolymer is as follows: dried polyethylene glycol, caprolactone and tin salt are reacted at a constant temperature under inert gas protection, then dissolved with solvent three, precipitated with solvent four and vacuum dried to obtain the crude copolymer.

6. The purification method according to claim 5, characterized in that, Solvent one and solvent three are each independently selected from one or more of dimethyl sulfoxide, chloroform, xylene, n-hexane, acetonitrile, dimethylformamide, ethyl acetate, dichloromethane, butanone, and ethanol; solvent two and solvent four are each independently selected from one or more of diethyl ether, n-octane, isohexane, toluene, or petroleum ether.

7. The purification method according to claim 5, characterized in that, The mass ratio of polyethylene glycol to caprolactone is (20~80): (20~80); the mass fraction of tin salt is 0.5~2wt%; the tin salt is selected from one or more of tin methanesulfonate, dioctyltin, triphenyltin, triethyltin, tetramethyltin, dibutyltin dilaurate or stannous octoate.

8. The purification method as described in claim 5, characterized in that, The isothermal reaction is carried out at a temperature of 90~120 ℃ for 10~20 h; the inert gas is one or more of nitrogen or rare gases.

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