A method for preparing a polyethylene glycol monomethyl ether-polylactic acid block copolymer

Abstract

The application discloses a preparation method of a polyethylene glycol monomethyl ether-polylactic acid block copolymer, and the method comprises the following steps: using a mixture of antimony trioxide and phosphoric acid as a catalyst during preparation of lactide, and combining with a deep hydrolysis process to improve the optical purity of the lactide; and when the lactide and polyethylene glycol monomethyl ether are subjected to ring-opening polymerization to generate the polyethylene glycol monomethyl ether-polylactic acid block copolymer, the solution polymerization reaction system is combined with a composite aluminum catalyst and a colloidal fractionation purification process to accurately control the molecular weight of the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer, improve the finished product yield, and eliminate the toxic side effects caused by the tin residue exceeding the standard in the existing polyethylene glycol monomethyl ether-polylactic acid block copolymer process on the human body.

Description

Technical Field

[0001] This invention belongs to the field of polymer material synthesis, specifically relating to a method for preparing a polyethylene glycol monomethyl ether-polylactic acid block copolymer. Background Technology

[0002] In recent years, the cosmetic minimally invasive surgery market has grown rapidly, with injectable fillers becoming the mainstay of the industry. Polyethylene glycol monomethyl ether-polylactic acid block copolymer (mPEG-PLLA) is favored by the industry due to its good biocompatibility, biodegradability, and amphiphilicity.

[0003] Most publicly available processes for preparing polyethylene glycol monomethyl ether-polylactic acid block copolymers (PEG-PLA) start with purchased lactide, use stannous octoate as a catalyst, and employ bulk polymerization, controlling the molecular weight of the product by adding polymerization inhibitors. This process involves high reaction temperatures in the later stages, reaching around 180°C, and reaction times exceeding 4 hours. Furthermore, the introduction of impurities from the lactide and the addition of polymerization inhibitors exacerbate side reactions, making precise control of the polymer molecular weight difficult, resulting in a wide molecular weight distribution, deviations in optical rotation, and difficulty in removing residual polymerization inhibitors and catalysts. Although refining processes can narrow the molecular weight distribution and reduce residual polymerization inhibitors, the yield is less than 40%, leading to high production costs. Moreover, the issues of precise molecular weight control, optical rotation deviations, and tin residues remain unresolved.

[0004] For example, Chinese patent CN201510593332.X proposes that amphiphilic polylactic acid block copolymers have superior performance compared to poly-L-lactic acid in injectable filler applications, and specifies the use of poly-L-lactic acid block copolymers with a molecular weight of 10,000 to 500,000. Due to the sensitizing nature of human skin, the production of injectable fillers requires high-purity raw materials and stringent control over heavy metal and chemical reagent residues to ensure clinical application. Furthermore, the molecular weight and dispersion coefficient of poly-L-lactic acid directly determine the product yield during manufacturing. Therefore, qualified injectable filler raw materials need to possess the following characteristics: high purity, low residue, controllable molecular weight, and narrow molecular weight distribution of poly-L-lactic acid block copolymers.

[0005] Chinese patent CN 104892909 discloses a method for preparing a product using polyethylene glycol monomethyl ether and D,L-lactide as reactants and stannous octoate as a catalyst via melt polycondensation. After the reaction is complete, the product is obtained by dissolving in dichloromethane and crystallizing in diethyl ether 1 to 4 times. This method is a commonly used method for preparation. However, the reaction time is as long as 12 to 14 hours, resulting in a product with a low molecular weight. The long reaction time causes transesterification, leading to poor optical purity of the product and a yield of less than 80%.

[0006] Chinese patent CN 1111253A discloses a process that uses triisobutylaluminum as a catalyst to initiate bulk or solution copolymerization of lactone (or lactone) and polyether glycol under nitrogen protection at 60-220°C. The molecular weight is controlled by using a fatty alcohol with 12-24 carbon atoms as a molecular weight regulator. This process avoids the residue of heavy metal tin and controls the molecular weight of the polymer product polyD,L-lactide. However, the addition of fatty alcohol terminates the polymerization reaction prematurely, resulting in a wide molecular weight distribution. At the same time, the introduction of fatty alcohol chains increases the residue in the polymer.

[0007] Chinese patent CN 106995528 A discloses a method for refining polyethylene glycol monomethyl ether-polylactic acid block copolymer (mPEG-PDLLA) using a stepwise cooling process. This method narrows the molecular weight distribution of the polymer, resulting in small and uniform polymer micelles with excellent freeze-dried powder stability and good reconstitution effect. However, this process has a yield of less than 40%, high material loss, and high production costs.

[0008] In addition, the manufacturing methods of the aforementioned patented polyethylene glycol monomethyl ether-polylactic acid block copolymers mostly start with lactide. Commercially available L-lactide is basically an industrial product and does not pay attention to the high optical purity and low residue required for medical use. This defect has an adverse effect on the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer that is difficult to make up for in the later stages. Summary of the Invention

[0009] This invention starts with lactic acid and, through the implantation and integration of processes, first produces high-purity lactide, and then completes liquid-phase polymerization under a composite aluminum catalyst and a mild reaction temperature (below 145°C and reaction time less than 1 hour). The polymer colloid is then refined to obtain polyethylene glycol monomethyl ether-polylactic acid block copolymer with high optical purity and controllable molecular weight.

[0010] This invention provides a method for preparing a polyethylene glycol monomethyl ether-polylactic acid block copolymer, specifically including the following steps:

[0011] Step 1: Under the catalysis of a composite aluminum catalyst, lactide and polyethylene glycol monomethyl ether undergo ring-opening polymerization to generate polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.

[0012] Step 2: Polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid is purified to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer.

[0013] Preferably, the preparation process of lactide in step 1 includes the following steps:

[0014] Step 1) Dehydration of lactic acid to obtain oligolactic acid. First, under certain temperature and negative pressure conditions, the free water in the lactic acid is removed. Then, under the condition of a catalyst, the temperature is gradually increased and the pressure is decreased to remove the bound water in the lactic acid.

[0015] Preferably, the temperature for removing free water is 70–90°C, more preferably 75–85°C, for example 75°C, 78°C, 80°C, 82°C, or 85°C.

[0016] Preferably, the negative pressure for removing free water is -0.090 to -0.097 MPa, more preferably -0.093 to -0.097 MPa, such as -0.093 MPa, -0.094 MPa, -0.095 MPa, -0.096 MPa, and -0.097 MPa.

[0017] Preferably, the catalyst for removing bound water from lactic acid is a mixture of antimony trioxide and phosphoric acid. Compared with using antimony trioxide alone as a catalyst, the mixed catalyst can better reduce the cyclization of lactic acid oligomers into racemic lactide or the conversion to D-lactide, thereby improving the optical purity of L-lactide.

[0018] Preferably, in the mixed catalyst, the amount of antimony trioxide added is 0.75 to 0.85% of the mass of lactic acid, more preferably 0.75 to 0.80%, for example 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, or 0.80%.

[0019] Preferably, in the mixed catalyst, the amount of phosphoric acid added is 0.2% to 0.4% of the mass of lactic acid, more preferably 0.25% to 0.4%, for example 0.25%, 0.28%, 0.30%, 0.35%, 0.38%, or 0.40%.

[0020] Preferably, the starting temperature for removing bound water from lactic acid is 120–160°C, more preferably 140–160°C, for example 140°C, 145°C, 150°C, 155°C, or 160°C.

[0021] Preferably, in the process of removing lactic acid bound water, the heating and depressurization are carried out in a stepped manner, with each step having a temperature of 2 to 5°C, for example, 2°C, 3°C, 4°C, and 5°C. The pressure of each step is -0.01 to -0.03 MPa, for example, -0.01 MPa, -0.02 MPa, and -0.03 MPa.

[0022] Preferably, the final temperature for removing lactic acid bound water is 180–190°C, and the vacuum degree is ultimate vacuum.

[0023] Step 2) Oligolactic acid is cleaved and cyclized to produce lactide. After the lactic acid is dehydrated, the reaction vessel is first purged to atmospheric pressure with an inert gas, then the aqueous solution is removed, and a catalyst is added. The reaction is then cleaved and cyclized at a temperature above 200°C and a negative pressure below -0.095 MPa to obtain block lactide.

[0024] Preferably, the inert gas is selected from at least one of nitrogen, argon or helium, and more preferably nitrogen.

[0025] Preferably, the catalyst is antimony trioxide and glycerol.

[0026] Preferably, the amount of antimony trioxide added is 0.15% to 0.25% of the initial lactic acid mass, and more preferably, the amount of antimony trioxide added is 0.15% to 0.2% of the initial lactic acid mass, for example, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, or 0.20%.

[0027] Preferably, the amount of glycerol added is 3% to 8% of the initial lactic acid mass, more preferably 5% to 8%, for example 5%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%.

[0028] Preferably, the temperature above 200°C is 200°C to 260°C, more preferably 220°C to 250°C, and even more preferably 220°C to 240°C, such as 220°C, 225°C, 230°C, 235°C, and 240°C.

[0029] In existing lactide synthesis processes, the cleavage and cyclization of oligolactic acid into lactide requires prolonged high-temperature reactions, inevitably leading to transesterification side reactions. This results in the formation of partial meso lactide, affecting the optical rotation of lactide and subsequent polymerization reactions. Therefore, minimizing transesterification side reactions during synthesis and completely eliminating meso lactide during lactide purification are crucial.

[0030] This invention employs a composite high-efficiency catalytic system of antimony trioxide + phosphoric acid and antimony trioxide + glycerol, which are added in stages. Under the same temperature, this accelerates the reaction rate of the entire lactide synthesis process, reduces the change in optical rotation caused by transesterification due to continuous high temperature, and reduces the amount of lactide with altered optical rotation in crude lactide, thereby improving the optical purity and yield of L-lactide.

[0031] Step 3) The lactide obtained in step 2) is subjected to water extraction. The block lactide and water are added together according to the preset mass ratio, stirred and mixed evenly, and the aqueous solution is filtered off after standing.

[0032] Preferably, the mass ratio of block lactide to water is 1:1 to 1:3, more preferably 1:1.5 to 1:2.5, for example 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5.

[0033] Step 4) Hydrolyze the water-extracted lactide. Add the water-extracted lactide to warm water for deep hydrolysis.

[0034] Preferably, the mass ratio of lactide extracted by water to warm water is 1:2 to 4, more preferably 1:2 to 3, for example 1:2, 1:2.3, 1:2.5, 1:2.7, 1:3.

[0035] Preferably, the temperature of the warm water is 45-55°C, more preferably 48-53°C, for example 48°C, 49°C, 50°C, 51°C, 52°C, or 53°C.

[0036] Preferably, the hydrolysis time is 2 to 5 hours, more preferably 2.5 to 5 hours, for example 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, and 5.0 hours.

[0037] This invention completely eliminates meso-lactide in crude lactide through deep hydrolysis, thereby improving the optical purity of L-lactide and obtaining a high-purity monomer, which can then be further used to prepare polylactic acid with high optical purity.

[0038] Step 5) The hydrolyzed lactide is filtered to remove water, washed with organic solvent, and dried to obtain crude lactide.

[0039] Preferably, the organic solvent is selected from any one of ethanol, diethyl ether, and propanol, and more preferably ethanol.

[0040] Preferably, the drying method is air drying or oven drying, and the drying temperature is preferably below 65°C, more preferably below 60°C.

[0041] Step 6) Purify and refine the crude lactide. Add the prepared crude lactide and anhydrous ethanol to a crystallization purification vessel, dissolve and filter, allow the filtrate to crystallize overnight, then separate the solid and liquid phases to obtain lactide crystals, and dry under vacuum to obtain primary purified lactide. Then, purify and crystallize the primary purified lactide with ethyl acetate to obtain refined lactide.

[0042] Preferably, the mass ratio of crude lactide to anhydrous ethanol is 1:1 to 2, more preferably 1:1 to 1:1.5, for example 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5.

[0043] Preferably, the mass ratio of primary lactide to ethyl acetate is 1:0.7 to 1.5, more preferably 1:0.7 to 1.2, for example 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.15, 1:1.2.

[0044] Preferably, the dissolution temperature is 70-85°C, more preferably 70-80°C, for example 70°C, 72°C, 74°C, 76°C, 78°C, or 80°C.

[0045] Preferably, the crystallization temperature of the filtrate is 10–35°C, more preferably 10–30°C, for example 10°C, 15°C, 20°C, 25°C, or 30°C.

[0046] Preferably, the vacuum drying temperature is 45-60°C, more preferably 45-55°C, for example 45°C, 47°C, 50°C, 53°C, or 55°C.

[0047] This invention employs a multi-solvent alternating recrystallization purification process, utilizing the different solubilities of the solvents to effectively remove insoluble and soluble impurities, including free acid and water, and to improve the crystallinity of lactide, thus preparing high-purity lactide with low residues, laying a solid foundation for the stable and complete polymerization reaction in the later stages.

[0048] In one embodiment of the present invention, the preparation process of the polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid in step 1 includes the following steps:

[0049] Step 1-1: Add the refined lactide and polyethylene glycol monomethyl ether prepared in step 6) above into the polymerization reaction vessel, dry under vacuum, and then replace with an inert gas to remove moisture from the reaction system.

[0050] Preferably, in the mixture of refined lactide and polyethylene glycol monomethyl ether, the mass fraction of lactide is 97-99.5%, more preferably 97.5-99.5%, for example 97.5%, 98%, 98.5%, 99%, 99.5%.

[0051] Preferably, the vacuum drying temperature is 45-60°C, more preferably 45-55°C, for example 45°C, 47°C, 50°C, 53°C, or 55°C.

[0052] Preferably, the inert gas is selected from at least one of helium, argon, and nitrogen, and more preferably argon.

[0053] Preferably, the inert gas is replaced 2 to 5 times, more preferably 3 to 5 times, for example 3 times, 4 times, or 5 times.

[0054] Step 1-2: Add anhydrous xylene to the reaction system treated in Step 1-1, heat to dissolve, then add catalyst and heat to react to obtain polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.

[0055] Preferably, the mass ratio of anhydrous xylene to monomer is 1.5 to 2.5:1, more preferably 2.0 to 2.5:1, for example 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1.

[0056] Preferably, the temperature for the heating and melting process is controlled below 130°C, and more preferably below 120°C.

[0057] Preferably, the catalyst is a composite aluminum-based catalyst, more preferably the catalyst includes triisobutylaluminum, and even more preferably, the catalyst includes triisobutylaluminum, isobutylene, and xylene. More preferably, the mass ratio of triisobutylaluminum, isobutylene, and xylene is 1:2.5-3.0:0.1-0.2.

[0058] Preferably, based on the total mass of lactide and polyethylene glycol monomethyl ether, and calculated according to pure triisobutylaluminum, the amount of composite aluminum catalyst added is 0.15-2.0%, more preferably 0.15-1.0%, for example 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.42%, 0.45%, 0.5%, 0.75%, and 1.0%.

[0059] This invention employs a self-developed high-activity composite aluminum catalyst, which exhibits higher catalytic activity than commonly used stannous octoate, resulting in lower reaction temperatures and faster reaction rates. Ordinary aluminum catalysts, however, readily decompose or react with trace amounts of water and oxygen during use, leading to a decrease in activity. This invention, by combining isobutylene, xylene, and the aluminum catalyst in a composite manner, prevents the aluminum catalyst from reacting with trace amounts of water and oxygen, thereby maintaining its high activity and ensuring a stable polymerization process throughout the entire process—before, during, and after the polymerization reaction.

[0060] Preferably, the ring-opening polymerization reaction temperature is 110–145°C, more preferably 115–140°C, and even more preferably 120–140°C, for example 120°C, 125°C, 130°C, 135°C, and 140°C.

[0061] Preferably, the ring-opening polymerization reaction takes 0.5 to 1.5 hours, more preferably 0.5 to 1.0 hours, for example 0.5 hours, 0.75 hours, 0.8 hours, or 1.0 hours.

[0062] Preferably, polyethylene glycol monomethyl ether, refined lactide, and anhydrous xylene constitute the solution polymerization reaction system for the ring-opening polymerization reaction.

[0063] Preferably, the anhydrous solvent is selected from at least one of anhydrous xylene, decahydronaphthalene, or diphenyl ether, and more preferably anhydrous xylene.

[0064] Preferably, the mass ratio of the total mass of refined lactide and polyethylene glycol monomethyl ether to anhydrous xylene is 1:1.5 to 2.5. More preferably, the mass ratio of the total mass of refined lactide and polyethylene glycol monomethyl ether to anhydrous xylene is 1:1.5 to 2.2, for example, 1:1.5, 1:1.8, 1:2.0, 1:2.1, or 1:2.2.

[0065] In another embodiment of the present invention, the process of refining the polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer in step 2 includes the following steps:

[0066] Step 2-1, graded treatment of polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.

[0067] First, add the polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid obtained in steps 1-2 and dichloromethane to the purification reaction vessel, stir to dissolve, then add anhydrous ethanol and continue stirring. After the polyethylene glycol monomethyl ether-polylactic acid block copolymer is completely dissolved, slowly add anhydrous ethanol dropwise. Stop when a large amount of soft colloid appears in the solution, let it stand to clarify, and remove the supernatant.

[0068] Preferably, the mass ratio of polyethylene glycol monomethyl ether-polylactic acid block copolymer to dichloromethane is 1:4 to 8, more preferably 1:5 to 7, for example 1:5, 1:5.5, 1:6, 1:6.5, 1:7.

[0069] Preferably, the volume of anhydrous ethanol added is the same as the volume of dichloromethane.

[0070] Step 2-2: Purification of polyethylene glycol monomethyl ether-polylactic acid block copolymer soft colloid.

[0071] First, add an appropriate amount of anhydrous ethanol to the polyethylene glycol monomethyl ether-polylactic acid block copolymer soft colloid after the fractionation treatment in step 2-1, stir to precipitate, then separate the solid and liquid, dry the precipitate, and obtain the primary pure product of polyethylene glycol monomethyl ether-polylactic acid block copolymer.

[0072] The primary purified product of polyethylene glycol monomethyl ether-polylactic acid block copolymer and dichloromethane were added to a purification container and stirred to dissolve. The mixture was then filtered into a purification container in a Class 10,000 cleanroom. An appropriate amount of anhydrous ethanol was added under stirring to precipitate the product, resulting in solid-liquid separation. The precipitate was dried, sieved, and the fine powder was then vacuum-dried to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer.

[0073] Preferably, the filtration is a 0.2-micron pressure filtration.

[0074] Preferably, the temperature for vacuum drying the fine powder is 45-60°C, more preferably 45-55°C, for example 45°C, 47°C, 50°C, 53°C, or 55°C.

[0075] The fractional purification process of this invention can remove low molecular weight polymers, resulting in a narrower molecular weight distribution in the finished product. The fractional operation in this process is organically combined with conventional polylactic acid purification processes, effectively saving production costs while achieving the desired results.

[0076] The beneficial effects of this invention are:

[0077] In the preparation of lactide, this invention uses antimony trioxide and phosphoric acid, and antimony trioxide and glycerol as catalysts, respectively. The catalysts are added in two batches in two stages, which makes the molecular chain of oligolactic acid shorter, easier to cleave and cyclize, and reduces the change in optical rotation of lactide, thereby improving the optical purity and yield of L-lactide.

[0078] Second, in the preparation of lactide, the present invention adopts a unique deep hydrolysis process to eliminate meso lactide and further improve the optical purity of L-lactide.

[0079] Third, in the refining process of lactide, the present invention adopts a multi-solvent alternating recrystallization purification process to effectively remove impurities (such as free acid and water), improve the crystallinity of lactide, and further improve the purity of L-lactide.

[0080] IV. The residual lactide content of the lactide prepared by this invention is <10 PPM. The medical industry standard YY / T0661-2017 limits it to ≤3%; verification shows that the residual lactide in medical-grade polylactic acid sold by the internationally renowned polylactic acid manufacturer Corbion is <0.1%. The low residual lactide content of the lactide prepared by this invention avoids the problem of unstable mechanical properties caused by internal cracks in injection molded parts during subsequent processing, and also reduces the risk of aseptic inflammation caused by rapid hydrolysis of lactide in clinical applications.

[0081] Fifth, in the ring-opening polymerization process, this invention uses a unique composite aluminum-based catalyst to replace stannous octoate and ordinary aluminum-based catalysts, which improves the reaction activity and eliminates the problems of excessive tin residue and easy oxidation of aluminum-based catalysts caused by the use of stannous octoate in the prior art. It also eliminates the toxic side effects of tin on the human body and effectively solves the defects of mPEG-PLLA in medical applications.

[0082] VI. In the ring-opening polymerization process, this invention employs a solution polymerization system, which allows for a more complete reaction, lowers the reaction temperature, and shortens the reaction time. This effectively avoids side reactions such as transesterification caused by the high temperature and long reaction time of traditional processes, improves the optical purity of the polyethylene glycol monomethyl ether-polylactic acid block copolymer, and ensures a smooth metabolic pathway for the high-optical-purity L-lactic acid and polyethylene glycol monomethyl ether copolymer, thereby improving biocompatibility.

[0083] VII. In the colloidal purification process of polyethylene glycol monomethyl ether-polylactic acid block copolymer, this invention employs a staged purification process to remove low molecular weight polymers, resulting in a narrower molecular weight distribution in the finished product. Simultaneously, by precisely controlling the molecular weight and narrow molecular weight distribution of the polyethylene glycol monomethyl ether-polylactic acid block copolymer, the mechanical properties are more stable and the downstream product yield is higher in downstream processing applications. Furthermore, this invention does not add polymerization inhibitors or molecular weight regulators, reducing side reactions caused by polymerization inhibitors and high temperatures, and further narrowing the molecular weight distribution of the product.

[0084] 8. This invention first prepares high-purity monomers. Then, with the support of a solution polymerization system and a composite aluminum catalyst, the low-concentration reaction system can be rapidly and uniformly dispersed. Under suitable reaction temperatures, coordination polymerization proceeds simultaneously, and energy exchange in the solution reaction system is sufficient. This allows polymerization to be completed under reaction conditions below 145°C and in less than 1 hour, effectively avoiding side reactions such as transesterification caused by the high temperatures and long reaction times of traditional processes, resulting in polymers with high optical purity. Simultaneously, the low-concentration solution reaction system effectively maintains intermolecular motion in the later stages of polymerization, ensuring complete monomer conversion, effectively reducing lactide residue, and improving polymer yield. Attached Figure Description

[0085] Figure 1 This is the infrared spectrum of the sample from Example 4;

[0086] Figure 2 This is the NMR spectrum of the sample from Example 4. Detailed Implementation

[0087] The technical solution of the present invention will be further described below with reference to embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, it should be understood that the embodiments are merely exemplary and do not constitute a limitation on the scope of the present invention.

[0088] Example 1: Preparation of L-lactide Sample 1

[0089] 1.1 L-Lactic Acid Dehydration

[0090] 1.25 kg of 80% L-lactic acid was added to an L-lactide synthesis reactor and maintained at 80 °C and -0.095 MPa for 1.5 h to remove free water from the L-lactic acid. Then, the vacuum was closed, and 8.5 g of antimony trioxide and 1.5 mL of phosphoric acid were added. The initial temperature was 160 °C and -0.03 MPa, and the reaction was carried out for 0.5 h. The reaction was then increased in increments of 5 °C and -0.02 MPa, adjusted every 0.5 h, until a final treatment at 180 °C under ultimate vacuum for 1 h was achieved. The mixture was then purged with nitrogen to atmospheric pressure to remove the aqueous solution and further remove bound water from the L-lactic acid, yielding the oligomeric L-lactic acid reactant.

[0091] 1.2. Oligomeric L-lactic acid undergoes cleavage and cyclization to generate L-lactide.

[0092] Add 1.5 g of antimony trioxide and 50 mL of glycerol to the reactants, and then react under ultimate vacuum at 220 °C. Increase the temperature by 5 °C every 1 hour until about 70 mL of reactants remain, then stop the reaction to obtain blocky L-lactide.

[0093] 1.3 Aqueous extraction treatment of blocky L-lactide

[0094] Add 1.4-1.5L of purified water to the reaction vessel, stir and break up the lumps of L-lactide to ensure that the L-lactide and purified water are thoroughly mixed, and then filter out the aqueous solution.

[0095] 1.4. Extensive hydrolysis of L-lactide

[0096] The L-lactide extracted by water was poured into a stirred tank, 2L of purified water at 50℃ was added, and hydrolysis was carried out at 500rpm for 3h.

[0097] 1.5 Preparation of crude L-lactide

[0098] The aqueous solution in the hydrolysate was removed by filtration, and then 0.25 L of anhydrous ethanol was added for washing. The mixture was then air-dried at 60 °C to obtain crude L-lactide.

[0099] 1.6 Purification and refining of crude L-lactide

[0100] 800 g of crude L-lactide was added to a crystallization purification vessel with 1.15 L of anhydrous ethanol. The mixture was stirred and dissolved at 80 °C, then filtered. The filtrate was allowed to crystallize overnight at room temperature. Solid-liquid separation yielded L-lactide crystals. These crystals were then vacuum dried at 50 °C to obtain primary purified L-lactide. Next, 600 g of the primary purified L-lactide was added to a crystallization purification vessel with 0.7 L of anhydrous ethyl acetate. The mixture was dissolved at 80 °C and crystallized overnight at room temperature. Solid-liquid separation yielded L-lactide crystals, which were then vacuum dried at 50 °C to obtain purified L-lactide sample 1. The purity of the L-lactide was found to be as high as 99.95%.

[0101] Example 2: Preparation of L-lactide Sample 2

[0102] 2.1L-Lactic acid dehydration:

[0103] 1.25 kg of 80% L-lactic acid was added to an L-lactide synthesis reactor and maintained at 80 °C and -0.095 MPa for 1.5 h to remove free water from the L-lactic acid. Then, the vacuum was closed, and 7.5 g of antimony trioxide and 1.5 mL of phosphoric acid were added. The initial temperature was 160 °C and -0.03 MPa, and the reaction was carried out for 0.5 h. The temperature was then increased by 5 °C and -0.02 MPa in increments, adjusted every 0.5 h, until treatment was carried out at 180 °C under ultimate vacuum for 1 h. The pressure was then purged with nitrogen to atmospheric pressure to remove the aqueous solution and remove bound water from the L-lactic acid, yielding the oligomeric L-lactic acid reactant.

[0104] 2.2 Oligomeric L-lactic acid undergoes cleavage and cyclization to generate L-lactide:

[0105] Add 2.5 g of antimony trioxide and 50 mL of glycerol to the reactants, and then react under ultimate vacuum at 220 °C. Increase the temperature by 5 °C every 1 hour until about 70 mL of reactants remain, then stop the reaction to obtain blocky L-lactide.

[0106] The remaining steps were the same as in Example 1. Finally, the purity of L-lactide sample 2 was determined to be 99.9%. Comparative Example 1: Preparation of L-lactide as a control sample 1.

[0107] The experimental procedure was the same as in Example 1, the only difference being that phosphoric acid was not added as a catalyst for the dehydration of L-lactic acid. Finally, the purity of L-lactide compared to sample 1 was determined to be 97.5%.

[0108] Comparative Example 2: Preparation of L-lactide as a Comparative Sample 2

[0109] The experimental procedure was the same as that in Example 1, except that the antimony trioxide catalyst, which was added in both the L-lactic acid dehydration and oligo-L-lactic acid pyrolysis cyclization steps, was changed to be added all at once during the L-lactic acid dehydration step, with 10g of antimony trioxide added at once.

[0110] Comparative Example 3: Preparation of L-lactide as a Comparative Sample 3

[0111] The experimental procedure was the same as in Example 1, except that the deep hydrolysis of L-lactide was omitted. Instead, the water-extracted L-lactide was poured into a stirred tank, 2L of purified water was added for purification and pulverization, and then filtered. Then, the preparation of crude L-lactide proceeded.

[0112] Example 3: Determination of L-lactide Samples

[0113] 3.1 Determination of specific rotation of L-lactide samples

[0114] According to the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV), General Chapter 0621 - Determination of Optical Rotation, the L-lactide samples prepared in the examples and the comparative samples prepared in the comparative examples were measured. The results are shown in Table 1.

[0115] Table 1

[0116] sample Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Specific rotation (°) -287.8 -288.9 -278.9 -279.8 -280.5

[0117] As shown in Table 1, the specific rotation of the L-lactide sample prepared in the examples is lower than that of the comparative sample, indicating that the process of the present invention can improve the optical purity of L-lactide compared with the existing process (comparative process). The improvement in the optical purity of L-lactide lays a technical foundation for improving the quality of polyethylene glycol monomethyl ether-poly(L-lactic acid) block copolymer.

[0118] 3.2 Determination of Free Acids in L-Lactose Samples

[0119] 3.2.1 Method for determining free acid:

[0120] A. Standardization of sodium methoxide standard solution: Accurately weigh approximately 50 mg of benzoic acid into a 100 mL Erlenmeyer flask, add 25 mL of anhydrous methanol and two drops of 0.2% α-naphthol phthaloyl alcohol solution, slowly purge with dry N2, and start the stirrer to dissolve the sample (approximately 5 min). Then, titrate with an anhydrous methanol solution of approximately 0.02 mol / L sodium methoxide to be standardized until a pale blue endpoint is reached. The concentration of this sodium methoxide solution is calculated using the following formula:

[0121]

[0122] In the formula:

[0123] c-Sodium methoxide standard solution concentration (mol / L);

[0124] V - Volume (mL) of sodium methoxide standard solution consumed in the titration of the sample;

[0125] m B - Benzoic acid mass (mg);

[0126] The molecular weight of 122,1-benzoic acid.

[0127] B. Accurately weigh 1.8–2.0 g of L-lactide sample into a 100 mL Erlenmeyer flask, and titrate with standardized sodium methoxide solution according to the standardization procedure for sodium methoxide standard solution. The free acid content is calculated as follows:

[0128]

[0129] In the formula:

[0130] c-Sodium methoxide standard solution concentration (mol / L);

[0131] V - Volume (mL) of sodium methoxide standard solution consumed in the titration of the sample;

[0132] m - Sample mass (mg);

[0133] 90.08-L-lactic acid molecular weight.

[0134] 3.2.2 Determination of Free Acid Content in L-Lactose

[0135] The free acid content in the L-lactide samples prepared in the examples and the L-lactide comparative samples was determined according to the method in 3.2.1, and the results are shown in Table 2.

[0136] Table 2

[0137] Sample Name Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Free acid (%) 0.02 0.04 0.19 0.11 0.12

[0138] As shown in Table 2, the free acid content in the L-lactide samples prepared in the examples was significantly lower than that in the L-lactide control samples. This indicates that compared with the prior art (comparative process), the process of the present invention can significantly reduce the residual free acid in L-lactide. The reduction in residual free acid indicates an improvement in the purity of L-lactide, thus laying a technical foundation for improving the quality of polyethylene glycol monomethyl ether-poly(L-lactic acid) block copolymers.

[0139] Example 4: Preparation of mPEG-PLLA Sample 1

[0140] The target molecular weight of this sample was designed to be Mw = 95,000. The specific preparation process is as follows:

[0141] 4.1 Removal of moisture

[0142] Weigh 300g of L-lactide sample from Example 1 and 3.16g of polyethylene glycol monomethyl ether, add them to the polymerization reactor, dry them under vacuum at 50°C, and then purge them three times with argon gas to remove moisture from the reaction system.

[0143] 4.2 Ring-opening polymerization reaction

[0144] 0.75 L of anhydrous xylene was added to the reactor, mixed and stirred, and heated to 120 °C. The mixture was stirred at 120 °C to obtain an anhydrous xylene solution of L-lactide and polyethylene glycol monomethyl ether. Then, 8.0 mL of a 0.8 M composite aluminum catalyst (the mass ratio of the three components of the catalyst was: triisobutylaluminum:isobutylene:xylene = 1:2.8:0.14) (containing 1.2693 g of triisobutylaluminum) was added, and the mixture was heated to 140 °C and reacted for 0.5 h to obtain mPEG-PLLA colloid.

[0145] 4.3. Fractionation of mPEG-PLLA colloids

[0146] All the mPEG-PLLA colloids prepared in step 4.2 were added to a purification vessel and stirred to dissolve. Then, 1.2L of anhydrous ethanol was added. After stirring until completely dissolved, anhydrous ethanol was slowly added dropwise again until a large amount of soft colloids appeared in the solution. The solution was allowed to stand and clarify, and the supernatant was poured off to complete the fractionation.

[0147] 4.4 Purification of mPEG-PLLA soft colloids

[0148] The graded soft colloid was precipitated into a fine powder by adding an appropriate amount of anhydrous ethanol under stirring. The solid-liquid separation and air drying were then performed to obtain a primary purified mPEG-PLLA product. 285g of the primary purified mPEG-PLLA product and 1.5L of dichloromethane were added to a purification vessel and stirred to dissolve. The mixture was then filtered through a 0.2-micron pressure filter into a purification vessel in a Class 10,000 clean area. An appropriate amount of anhydrous ethanol was added under stirring to precipitate the fine powder. The solid-liquid separation, air drying, and sieving were then performed. The mixture was dried under vacuum at 55℃ for 24 hours to obtain 275g of the final mPEG-PLLA product.

[0149] Example 5: Preparation of mPEG-PLLA Sample 2

[0150] The target molecular weight of this sample was designed to be Mw = 135,000. The specific preparation process is as follows:

[0151] 5.1 Removal of moisture

[0152] Weigh 300g of the L-lactide sample from Example 1 and 2.23g of polyethylene glycol monomethyl ether, add them to the polymerization reactor, dry them under vacuum at 50°C, and then purge them three times with argon gas to remove moisture from the reaction system.

[0153] 5.2 Ring-opening polymerization reaction

[0154] 0.7 L of anhydrous xylene was added to the reactor, mixed and stirred, and heated to 120 °C. The mixture was stirred at 120 °C to obtain an anhydrous xylene solution of L-lactide and polyethylene glycol monomethyl ether. Then, 5.0 mL of a 0.8 M composite aluminum catalyst (the mass ratio of the three components of the catalyst was: triisobutylaluminum:isobutylene:xylene = 1:2.8:0.14) (containing 0.7933 g of triisobutylaluminum) was added, and the mixture was heated to 140 °C and reacted for 45 min to obtain mPEG-PLLA colloid.

[0155] 5.3. Fractionation of mPEG-PLLA colloids

[0156] All the mPEG-PLLA colloids prepared in step 5.2 were added to a purification vessel and stirred to dissolve. Then, 1.4L of anhydrous ethanol was added. After stirring until completely dissolved, anhydrous ethanol was slowly added dropwise again until a large amount of soft colloids appeared in the solution. The solution was allowed to stand and clarify, and the supernatant was poured off to complete the fractionation.

[0157] 5.4 Purification of mPEG-PLLA soft colloids

[0158] The graded soft colloid was precipitated into a fine powder by adding an appropriate amount of anhydrous ethanol under stirring. The solid-liquid separation and air drying were then performed to obtain a primary purified mPEG-PLLA product. 287.5g of the primary purified mPEG-PLLA product and 1.7L of dichloromethane were added to a purification vessel and stirred to dissolve. The mixture was then filtered through a 0.2-micron pressure filter into a purification vessel in a Class 10,000 clean area. An appropriate amount of anhydrous ethanol was added under stirring to precipitate the fine powder. The solid-liquid separation, air drying, and sieving were then performed. The mixture was dried under vacuum at 55℃ for 24 hours to obtain 275.6g of the final mPEG-PLLA product.

[0159] Example 6: Preparation of mPEG-PLLA sample 3

[0160] The target molecular weight of this sample was designed to be Mw = 165,000. The specific preparation process is as follows:

[0161] 6.1 Removal of moisture.

[0162] Weigh 300g of L-lactide sample from Example 1 and 1.82g of polyethylene glycol monomethyl ether, add them to the polymerization reactor, dry them under vacuum at 50°C, and then purge them three times with argon gas to remove moisture from the reaction system.

[0163] 6.2 Ring-opening polymerization reaction.

[0164] 0.65 L of anhydrous xylene was added to the reactor, mixed and stirred, and heated to 120 °C. The mixture was stirred at 120 °C to obtain an anhydrous xylene solution of L-lactide and polyethylene glycol monomethyl ether. Then, 3.6 mL of a 0.8 M composite aluminum catalyst (the mass ratio of the three components of the catalyst was: triisobutylaluminum:isobutylene:xylene = 1:2.8:0.14) (containing 0.5712 g of triisobutylaluminum) was added, and the mixture was heated to 140 °C and reacted for 50 min to obtain mPEG-PLLA colloid.

[0165] 6.3. Fractionation of mPEG-PLLA colloids.

[0166] All the mPEG-PLLA colloids prepared in step 6.2 were added to a purification vessel and stirred to dissolve. Then, 1.6L of anhydrous ethanol was added. After stirring until completely dissolved, anhydrous ethanol was slowly added dropwise again until a large amount of soft colloids appeared in the solution. The solution was allowed to stand and clarify, and the supernatant was poured off to complete the fractionation.

[0167] 6.4 Purification of mPEG-PLLA soft colloids.

[0168] The graded soft colloid was precipitated into a fine powder by adding an appropriate amount of anhydrous ethanol under stirring. The solid-liquid separation and air drying were then performed to obtain a primary purified mPEG-PLLA product. 283.9 g of the primary purified mPEG-PLLA product and 1.9 L of dichloromethane were added to a purification vessel and stirred to dissolve. The mixture was then filtered through a 0.2-micron pressure filter into a purification vessel in a Class 10,000 clean area. An appropriate amount of anhydrous ethanol was added under stirring to precipitate the fine powder. The solid-liquid separation, air drying, and sieving were then performed. The mixture was dried under vacuum at 55°C for 24 h to obtain 273.1 g of the final mPEG-PLLA product.

[0169] Example 7: Preparation of mPEG-PLLA Sample 4

[0170] The experimental procedure is the same as in Example 4, with the only difference being:

[0171] In the ring-opening polymerization step, 7.1 mL of 0.9 M composite aluminum catalyst was added, wherein the mass ratio of the three components of the catalyst was: triisobutylaluminum: isobutylene: xylene = 1:2.5:0.1 (including 1.2673 g of triisobutylaluminum).

[0172] Example 8: Preparation of mPEG-PLLA sample 5

[0173] The experimental procedure was the same as that in Example 4, except that: after adding the composite aluminum catalyst to the reaction vessel, the temperature was raised to 135℃ and reacted for 50 min to obtain mPEG-PLLA colloid.

[0174] Comparative Example 4: Preparation of mPEG-PLLA as a control sample 1

[0175] The experimental procedure was the same as that in Example 4, except that the mass ratio of the catalyst components in 8.0 mL of 0.8 M aluminum catalyst was: triisobutylaluminum: xylene = 1:4.4 (containing 1.2693 g of triisobutylaluminum).

[0176] Comparative Example 5: Preparation of mPEG-PLLA Sample 2

[0177] The experimental procedure is the same as that in Example 4, except that:

[0178] In the ring-opening polymerization step, anhydrous xylene was not added, and bulk polymerization was used. The monomers of L-lactide and polyethylene glycol monomethyl ether were completely melted by stirring at 120°C. Then, the temperature was raised to 140°C, 0.98 g of stannous octoate was added, and the reaction was carried out at 160°C for 12 h to obtain mPEG-PLLA.

[0179] Comparative Example 6: Preparation of mPEG-PLLA Sample 3

[0180] The target molecular weight of this sample was designed to be Mw = 95,000. The specific preparation process is as follows:

[0181] 1) Removal of moisture.

[0182] Weigh 300g of L-lactide sample from Example 1, 3.16g of polyethylene glycol monomethyl ether, and 0.6g of lauryl alcohol as a molecular regulator, add them to a polymerization reactor, dry them under vacuum at 50°C, and then remove the moisture from the reaction system by purging with argon gas three times.

[0183] 2) Ring-opening polymerization reaction.

[0184] The mixture was stirred and heated to 120°C. The monomers of L-lactide, polyethylene glycol monomethyl ether, and lauryl alcohol were completely melted at 120°C. Then the temperature was raised to 140°C, 0.63 g of stannous octoate was added, and the mixture was heated to 160°C and reacted for 12 h to obtain mPEG-PLLA.

[0185] 3) Purification of mPEG-PLLA.

[0186] 1.4 L of dichloromethane was added to the reaction vessel and stirred to dissolve. The solution was then transferred to a purification vessel, where an appropriate amount of anhydrous ethanol was added under stirring to precipitate a fine powder. The solid-liquid mixture was separated and air-dried to obtain a primary purified mPEG-PLLA product. 260.5 g of the primary purified mPEG-PLLA product was added to the purification vessel with 1.4 L of dichloromethane and stirred to dissolve. The mixture was then filtered through a 0.2-micron pressure filter into a purification vessel in a Class 10,000 cleanroom. An appropriate amount of anhydrous ethanol was added under stirring to precipitate a fine powder. The solid-liquid mixture was separated, air-dried, sieved, and dried under vacuum at 55°C for 24 h to obtain 227.4 g of the final mPEG-PLLA product.

[0187] Example 9: Determination of mPEG-PLLA Samples

[0188] 9.1 Infrared Spectroscopy for Determination of mPEG-PLLA Samples

[0189] The mPEG-PLLA sample 1 prepared in Example 4 was determined by infrared spectroscopy according to General Chapter 0402 of the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV). The results are shown in Table 3 and... Figure 1 .

[0190] Table 3

[0191]

[0192] Table 3 and Figure 1 The results are shown as the group composition and infrared spectrum of sample 1 prepared in Example 4.

[0193] 9.2 Determination of mPEG-PLLA samples by proton nuclear magnetic resonance (NMR)

[0194] According to the nuclear magnetic resonance spectroscopy method in General Chapter 0441 of the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV), deuterated trichloromethane was used as the deuterated solvent to determine the mPEG-PLLA sample 1 prepared in Example 4. The results are shown below. Figure 2 .

[0195] Figure 2 The results showed characteristic peaks at 5.1-5.3 (-CH-), 3.5-3.8 (-CH2-), and 1.4-1.7 (-CH3). The NMR spectrum indicated that mPEG-PLLA block copolymers were successfully prepared from polyethylene glycol monomethyl ether and L-lactide. The relatively small peak area at 3.5-3.8 (-CH2-) in the spectrum confirms the low proportion of polyethylene glycol monomethyl ether in the copolymer. Furthermore, the absence of impurity peaks (except for the solvent peak) indicates high copolymer purity. Figure 1 The infrared spectrum further indicates that the copolymer is mPEG-PLLA.

[0196]

[0197] 9.3 Determination of specific rotation of mPEG-PLLA samples

[0198] According to the method for optical rotation determination in General Chapter 0621 of the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV), chloroform was used as the solvent to prepare a 0.01 g / mL solution for determination of mPEG-PLLA in the examples and comparative samples. The results are shown in Table 4.

[0199] Table 4

[0200]

[0201] As shown in Table 4, the specific rotation of the mPEG-PLLA samples prepared using the process of this invention is all below -155° and above -160°, meeting the specific rotation requirements (-155° to -160°) for mPEG-PLLA products in YY / T 0661-2017 "Semi-crystalline Poly(L-lactide) Polymers and Copolymers for Surgical Implants," and the reaction conditions are mild. In contrast, the specific rotation of the mPEG-PLLA comparative samples prepared using the existing process is all above -155°. Prolonged high temperatures lead to transesterification, altering the optical rotation and causing the final product to fail to meet the specific rotation requirements for mPEG-PLLA products in YY / T 0661-2017. This indicates that the purity of the mPEG-PLLA product prepared by the process of this invention is higher than that prepared by the existing process.

[0202] It should be noted that the copolymer of the present invention has a polyethylene glycol monomethyl ether molar content of <3%, and polyethylene glycol monomethyl ether is a non-chiral compound. Therefore, the polyethylene glycol monomethyl ether-poly(L-lactic acid) block copolymer can still be classified according to the standard of poly(L-lactide).

[0203] 9.4 Detection of residual polymerization ring-opening catalyst in mPEG-PLLA samples

[0204] Take 0.25 g of mPEG-PLLA sample and place it in a polytetrafluoroethylene digestion vessel. Add 6.0 mL of nitric acid and 2.0 mL of concentrated hydrogen peroxide solution, cover with the inner cap, tighten the outer cap, and place in a microwave digester for digestion. After complete digestion, remove the inner digestion vessel and place it on a hot plate to slowly heat until the reddish-brown gas dissipates. Carefully transfer the digestion solution from the vessel to a 100 mL volumetric flask with ultrapure water and dilute to the mark. Shake well to obtain the test solution. Prepare a reagent blank solution using the same method. Determine the residual amounts of tin or aluminum in the example and comparative sample samples by inductively coupled plasma mass spectrometry according to General Chapter 0412 of the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV). The determination results are shown in Table 5.

[0205] Table 5

[0206]

[0207] As shown in Table 5, the tin residue in Comparative Examples 5 and 6 was relatively high, significantly exceeding the limit of Sn < 150 ppm for catalyst residue in the YY / T0661-2017 standard. In contrast, the tin content in the samples of this invention was 0 ppm, and the aluminum residue was less than 10 ppm. This indicates that the process of this invention does not have the problem of tin residue in mPEG-PLLA. Furthermore, since trace amounts of aluminum can be excreted through the kidneys via normal human metabolism, the safe clinical application of mPEG-PLLA is ensured.

[0208] 9.5 Determination of L-lactide Residue in mPEG-PLLA

[0209] 9.5.1 Determination of L-lactide Residue

[0210] Accurately weigh an appropriate amount of butyl acetate, dissolve it in dichloromethane, and prepare a solution containing approximately 0.125 mg per mL as the internal standard solution. Accurately weigh approximately 0.1 g of the test sample, place it in a 10 mL volumetric flask, add 2 mL of the internal standard solution, dissolve in dichloromethane, dilute to the mark, and shake well to prepare the test solution. Separately, accurately add an appropriate amount of L-lactide to an appropriate amount of the internal standard solution, dissolve in dichloromethane, and prepare a solution containing approximately 100 μg of L-lactide and 25 μg of butyl acetate per mL as the control solution. Determine the concentration according to General Chapter 0521-Gas Chromatography in the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV). Use a chromatographic column with 5% phenyl-methylpolysiloxane (or similar polarity) as the stationary phase, a column temperature of 135℃, an injection port temperature of 250℃, and a detector temperature of 300℃. Take 3 μL of the test solution and the control solution and inject them into the gas chromatograph. Calculate the residual amount of L-lactide by peak area using the internal standard method.

[0211] 9.5.2 Determination of L-lactide Residue

[0212] The L-lactide in the mPEG-PLLA examples and comparative samples was determined according to the determination method in 9.5.1, and the results are shown in Table 6.

[0213] Table 6

[0214]

[0215] As shown in Table 6, the residual L-lactide in the mPEG-PLLA comparative samples prepared using existing processes is higher than 10 ppm, with Comparative Example 6 reaching as high as 23 ppm. In contrast, the L-lactide content in the mPEG-PLLA example samples prepared using the process of this invention is lower than 3 ppm. This indicates that the process of this invention can significantly reduce the residual L-lactide content during the preparation of mPEG-PLLA.

[0216] 9.6 Determination of molecular weight of mPEG-PLLA samples

[0217] 9.6.1 Methods for determining molecular weight and its distribution

[0218] Accurately weigh an appropriate amount of sample, dissolve it in tetrahydrofuran to prepare a solution containing approximately 3 mg per mL, shake, and let stand overnight at room temperature to obtain the test solution. Separately, take appropriate amounts of five polystyrene molecular weight reference standards (the molecular weight range should include that of the test sample), dissolve them in tetrahydrofuran to prepare a solution containing approximately 3 mg per mL, shake, and obtain the reference solutions. Determine the molecular weight according to General Chapter 0514 - Size Exclusion Chromatography of the 2020 edition of the Pharmacopoeia of the People's Republic of China (Part IV), using a gel permeation column, tetrahydrofuran as the mobile phase, and a differential refractive index detector at 35℃. Inject 20 μL of acetonitrile into the liquid chromatograph, record the chromatogram, and ensure the theoretical plate number (based on the acetonitrile peak) is not less than 10,000. Inject 20 μL of each of the above reference solutions into the liquid chromatograph, record the chromatogram, and calculate the regression equation using GPC software. Take 20 μL of the test solution and determine it using the same method. Calculate the weight-average molecular weight, number-average molecular weight, and molecular weight distribution of the test sample using GPC software.

[0219] 9.6.2 Determination of the molecular weight of mPEG-PLLA samples

[0220] The molecular weights of the mPEG-PLLA examples and comparative samples were determined according to method 9.6.1, and the results are shown in Table 7.

[0221] Table 7

[0222]

[0223] As shown in Table 7, the measured molecular weights of the mPEG-PLLA samples prepared using the process of this invention are close to the target molecular weights, with deviations all below 2%, and the dispersion coefficients are all <2.0. In contrast, the measured molecular weights of the comparative mPEG-PLLA samples prepared using existing processes are all lower than the target molecular weight range, with deviations of approximately 10%, and the dispersion coefficients are all >2.0. This indicates that the process of this invention can accurately control the molecular weight of mPEG-PLLA. This is because the use of a composite aluminum catalyst makes the liquid-phase polymerization process more uniform and controllable, effectively avoiding side reactions and improving the controllability of the target product's molecular weight. Simultaneously, the fractional purification technology effectively removes low-molecular-weight polymers from the mPEG-PLLA colloid, resulting in a narrower molecular weight distribution in the final product.

[0224] To investigate the effect of molecular weight regulators, the present invention conducted an experiment in Comparative Example 6. The results showed that, compared with Comparative Example 5, the addition of the molecular weight regulator lauryl alcohol could reduce the molecular weight and achieve the effect of molecular weight regulation. However, the molecular weight dispersion coefficient of the mPEG-PLLA sample was large, which affected the application of mPEG-PLLA, and there was a risk of lauryl alcohol residue in the product.

[0225] In addition, the molecular weight and molecular weight dispersion coefficient of the mPEG-PLLA example samples showed small deviations and good data parallelism, indicating that the process of the present invention has excellent reproducibility and stability.

[0226] 9.7 Statistical analysis of the yield of mPEG-PLLA samples

[0227] The yields of the finished products from the mPEG-PLLA examples and comparative samples were statistically analyzed, and the results are shown in Table 8.

[0228] Table 8

[0229]

[0230] As shown in Table 8, the yields of mPEG-PLLA samples prepared using the process of this invention are all above 90.0%, indicating a high final product yield. In contrast, the yields of comparative samples prepared using existing processes are approximately 80%, with comparative example 6, which added a molecular weight regulator, having a yield of only 75%. This demonstrates that the process of this invention can significantly improve the yield of mPEG-PLLA and enhance the quality of the mPEG-PLLA samples.

[0231] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a polyethylene glycol monomethyl ether-polylactic acid block copolymer, characterized in that: The preparation method includes: Step 1: Under the catalysis of a composite aluminum catalyst, lactide and polyethylene glycol monomethyl ether undergo ring-opening polymerization to generate polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid. The composite aluminum catalyst includes triisobutylaluminum, isobutylene and xylene, and the lactide is L-lactide. Step 2: Polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid is purified to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer.

2. The preparation method according to claim 1, characterized in that: The mass ratio of triisobutylaluminum, isobutylene, and xylene is 1:2.5~3.0:0.1~0.2; the amount of the composite aluminum catalyst added, based on triisobutylaluminum, is 0.15-2.0% of the total mass of the lactide and the polyethylene glycol monomethyl ether.

3. The preparation method according to claim 1, characterized in that: Step 1 includes dissolving the lactide and the polyethylene glycol monomethyl ether in an anhydrous solvent to carry out a ring-opening polymerization reaction.

4. The preparation method according to claim 3, characterized in that: The solvent is selected from at least one of anhydrous xylene, decahydronaphthalene, or diphenyl ether.

5. The preparation method according to claim 4, characterized in that: The solvent is anhydrous xylene.

6. The preparation method according to claim 5, characterized in that: The total mass ratio of lactide and polyethylene glycol monomethyl ether to anhydrous xylene is 1:1.5~2.

5.

7. The preparation method according to claim 3, characterized in that: In the lactide and polyethylene glycol monomethyl ether, the mass fraction of lactide is 97-99.5%.

8. The preparation method according to claim 3, characterized in that: The ring-opening polymerization reaction is carried out at a temperature of 110~145℃; The reaction time is 0.5~1.5 h.

9. The preparation method according to claim 8, characterized in that: The ring-opening polymerization reaction is carried out at a temperature of 120~140℃.

10. The preparation method according to claim 8, characterized in that: The reaction time is 0.5~1 h.

11. The preparation method according to claim 1, characterized in that: The preparation method of lactide in step 1 includes the following steps: Step 1), lactic acid is dehydrated to obtain oligolactic acid; Step 2), oligolactic acid is cleaved and cyclized to generate lactide; Step 3), the lactide obtained in step 2) is subjected to water extraction; Step 4) Hydrolyze the lactide after water extraction; Step 5) The hydrolyzed lactide is sequentially filtered to remove water, washed with organic solvent, and dried to obtain crude lactide; Step 6) The crude lactide is purified and refined. The catalyst in step 1) is antimony trioxide and phosphoric acid, and the catalyst in step 2) is antimony trioxide and glycerol.

12. The preparation method according to claim 11, characterized in that: In step 4), lactide is added to water at 45-55°C and hydrolyzed for 2-4 hours. The mass ratio of lactide to water is 1:2~4.

13. The preparation method according to claim 11, characterized in that: In step 1), the mass of antimony trioxide in the catalyst is 0.75-0.85% of the mass of lactic acid, and the mass of phosphoric acid is 0.2-0.4% of the mass of lactic acid.

14. The preparation method according to claim 11, characterized in that: In step 2), the mass of antimony trioxide in the catalyst is 0.15 to 0.25% of the mass of lactic acid.

15. The preparation method according to claim 1, characterized in that: Step 2 includes a fractional purification process for the polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.

16. The polyethylene glycol monomethyl ether-polylactic acid block copolymer obtained by the preparation method according to any one of claims 1-15.

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