A method of preparing a random PLGA

Abstract

This invention provides a method for preparing random PLGA, belonging to the field of polymer preparation technology. Addressing the problems of large differences in the reactivity ratios of lactide and glycolide, the tendency of traditional polymerization to produce block copolymers, and low molecular weight, this invention employs pulsed microwave pretreatment of a mixture of monomers and an alkaline earth metal catalyst. The microwave dipole polarization effect is used to achieve homogeneous eutectic melting and remove trace amounts of moisture. Subsequently, the melt is fed into a conical twin-screw extruder, and a specific structured amine metal catalyst is injected simultaneously to construct a bimetallic synergistic catalytic system. The large-volume ligands of the amine metal catalyst create steric hindrance, inhibiting preferential coordination of glycolide, while the electron-donating effect increases the ring-opening rate of lactide, causing the apparent polymerization rates of the two monomers to converge. This invention features a simple process and high catalytic efficiency, providing a new approach for the green preparation of high-performance PLGA.

Description

Technical Field

[0001] This invention belongs to the field of polymer preparation technology, and particularly relates to a method for preparing random PLGA. Background Technology

[0002] Poly(lactic-co-glycolic acid) (PLGA) is an important biomedical polymer material that combines the advantages of both polylactic acid (PLA) and polyglycolic acid (PGA). PLGA exhibits excellent biocompatibility and biodegradability; its degradation products, lactic acid and glycolic acid, can participate in human metabolism, ultimately being converted into carbon dioxide and water and excreted from the body. Therefore, it is widely used in pharmaceuticals, medical devices, and industrial fields. PLGA is typically an amorphous random copolymer with a glass transition temperature between 40 and 60°C. By adjusting the monomer ratio of lactide (LA) to glycolide (GA), polymers with different properties can be obtained (e.g., PLGA 75:25 indicates that the copolymer consists of 75% lactic acid segments and 25% glycolic acid segments). Currently, to meet the strength requirements of high molecular weight PLGA in the medical field, the industrial process mainly uses ring-opening polymerization (ROP), which involves polymerization of LA and GA as monomers under negative pressure in a metal coordination catalysis system.

[0003] Several PLGA preparation processes have been reported in the prior art. For example, a patent from Central South University (publication number CN106432699 A) discloses an industrial production process for injectable PLGA, using a one-pot polymerization system of stannous octoate and dodecanol. After purification by washing with organic solvents, the product has a weight-average molecular weight (Mw) of approximately 50,000 g / mol and an intrinsic viscosity of approximately 0.5 dL / g. This process uses high-temperature polymerization, leaving a large amount of monomer residue after the reaction, which needs to be removed by solvent washing. A patent from Nanjing Weier Pharmaceutical Co., Ltd. (publication number CN 114920919 A) discloses a method for preparing crude PLGA through high-temperature polymerization, combined with multiple "dissolution-co-precipitation" and drying spray processes to remove residual monomers and solvents. Shandong Guyuchun (publication number CN115386070 A) proposed that under a pressure of 0.2~0.5 MPa, combined with a specific gradient temperature program (prepolymerization at 100~110℃, polymerization at 170~180℃) and a diluted catalyst system, a weight-average molecular weight of 43,941 g / mol was synthesized.

[0004] Comprehensive analysis reveals significant limitations in existing PLGA polymerization processes regarding reaction condition control and product performance balance. On one hand, conventional heating and dehydration processes are time-consuming and prone to monomer pyrolysis, making it difficult to effectively remove bound water from the catalyst. Residual moisture can trigger chain transfer side reactions, hindering the increase of polymer molecular weight. On the other hand, due to the significant difference in the polymerization reactivity ratios of glycolide and lactide monomers, crystalline block copolymers are easily formed under traditional catalytic systems, making it difficult to obtain highly randomized PLGA. To address these issues, this invention proposes a method for preparing randomized PLGA. Summary of the Invention

[0005] To address the gap in polymerization rates between lactide and glycolide and to synthesize random copolymers, this invention proposes a method for preparing random PLGA. This method employs a dual-catalytic system of alkaline earth metal and amine metal, uses microwave treatment of raw materials, and conducts the reaction using a conical twin-screw extruder.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides a method for preparing random PLGA, comprising the following steps: Lactide, glycolide and alkaline earth metal catalyst were mixed and subjected to pulsed microwave treatment to melt them into a homogeneous liquid. The homogeneous liquid is added to a conical twin-screw extruder, and an amine metal catalyst is injected into the extruder to initiate a polymerization reaction, thereby obtaining random PLGA.

[0007] Furthermore, by weight, the amounts of each raw material are: 1-150 parts of lactide, 1-150 parts of glycolide, 0.001-0.3 parts of alkaline earth metal catalyst, and 0.001-0.3 parts of amine metal catalyst.

[0008] Furthermore, by weight, the amounts of each raw material are: 50-85 parts of lactide, 15-50 parts of glycolide, 0.05-0.2 parts of alkaline earth metal catalyst, and 0.01-0.2 parts of amine metal catalyst.

[0009] Furthermore, the alkaline earth metal catalyst is magnesium lactate.

[0010] Further, the structural formula of the amine-based metal catalyst is M[N(CH2CH3)2][N(CH3)(OCH2CH3)], wherein M is selected from Zn, Ca or Mg; preferably, the structural formula of the amine-based metal catalyst is Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)].

[0011] Furthermore, the preparation method of the amine-based metal catalyst is as follows: Under an inert atmosphere, n-butyllithium was added dropwise to an anhydrous toluene solution of diethylamine and N-methyl-O-ethylhydroxylamine, and the mixture was allowed to react completely to obtain a mixed amino-lithium solution. Subsequently, the mixed amino-lithium solution was added dropwise to a toluene suspension of anhydrous metal chloride, and the mixture was heated under reflux. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the clear filtrate was collected. The toluene solvent was removed by high-vacuum distillation to obtain the amino-metal catalyst.

[0012] Furthermore, the temperature of the heating reflux is 60–80°C.

[0013] Furthermore, the conditions for the pulsed microwave treatment are: ambient pressure, microwave power of 100-300W, temperature of 80-140℃, and treatment time of 1-5 minutes.

[0014] Furthermore, the microwave power is 180–280W, the temperature is 105–135℃, and the processing time is 2–5 minutes.

[0015] Furthermore, the reaction conditions inside the conical twin-screw extruder are: temperature of 140–200°C, material residence time of 1–5 minutes, and screw speed of 10–200 rpm.

[0016] Furthermore, the temperature is 155–195℃, the material residence time is 5 minutes, and the screw speed is 40–180 rpm.

[0017] Furthermore, the lactide is selected from one of L-lactide, D-lactide, and D,L-lactide.

[0018] Furthermore, the polymerization reaction is carried out at a temperature of 175–185°C for a reaction time of 10–20 min.

[0019] Furthermore, the method is carried out in an inert gas atmosphere, wherein the inert gas is nitrogen, argon or helium.

[0020] In the preparation method of random PLGA of this invention, the dipole polarization effect of microwaves is used to achieve homogeneous heating and eutectic melting of glycolide and lactide monomers, which are then uniformly dispersed together with an alkaline earth metal catalyst (magnesium lactate). Simultaneously, the high-frequency oscillation of the microwave field promotes the vaporization and removal of trace amounts of water in the system, reducing the interference of water molecules on the chain transfer initiation stage and providing an anhydrous environment for subsequent random copolymerization. Then, an amine metal catalyst is introduced into the system to construct a bimetallic catalytic system with the alkaline earth metal catalyst. The diethylamino and N-methyl-O-ethylhydroxyamino ligands in the amine metal catalyst generate steric hindrance, restricting the preferential coordination of glycolide with its smaller spatial volume. At the same time, the electron-donating effect of heteroatoms in the ligands enhances the nucleophilicity of the metal center, increasing the ring-opening rate of lactide. The bimetallic synergistic catalytic mechanism compensates for the intrinsic activity differences between monomers, making the apparent polymerization rates of lactide and glycolide tend to be consistent. As the polymerization reaction proceeds, the viscosity of the system continues to increase, which leads to impeded mass transfer. This invention uses an extruder for continuous reaction and utilizes the shearing and surface renewal effects of the screw to maintain the micro-mixing state of the system, ensuring that the catalyst and monomer are in continuous homogeneous contact in the high-viscosity melt, thus avoiding the induction of block structures due to local monomer concentration imbalance.

[0021] Compared with the prior art, the present invention has the following advantages and technical effects: 1. This invention uses pulsed microwave to process monomers, utilizing the dipole polarization effect of microwaves to achieve homogeneous eutectic melting of materials, while simultaneously promoting the vaporization and removal of trace amounts of bound water within the system.

[0022] 2. This invention constructs a dual-catalytic system of alkaline earth metal and amine metal, abandoning the commonly used external alcohol initiator in traditional ring-opening polymerization. Instead, an amine metal catalyst is added during the reaction extrusion process. The interaction between the alkaline earth metal catalyst and the amine metal catalyst improves the conversion rate of lactide, compensating for the difference in ring-opening reaction rates between lactide and glycolide. This results in the synthesized PLGA being closer to random copolymerization than block copolymerization, and exhibiting good mechanical properties.

[0023] 3. The catalyst raw materials used in this invention are readily available and the synthesis route is simple; at the same time, the constructed PLGA polymerization process is streamlined, has high catalytic efficiency, and significantly shortens the reaction time. Attached Figure Description

[0024] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The NMR C spectrum of the PLGA synthesized in Example 1 of this invention is shown.

[0025] Figure 2The NMR spectrum of the PLGA synthesized in Example 1 of this invention is shown.

[0026] Figure 3 This is the molecular weight gel permeation chromatography (APC) chromatogram of PLGA synthesized in Example 1 of this invention. Detailed Implementation

[0027] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0028] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0029] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0030] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0031] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0032] This invention provides a method for preparing random PLGA, comprising the following steps: Lactide, glycolide and alkaline earth metal catalyst were mixed and subjected to pulsed microwave treatment to melt them into a homogeneous liquid. A homogeneous liquid is added to a conical twin-screw extruder, and an amine metal catalyst is injected into the extruder to initiate a polymerization reaction, thereby producing random PLGA.

[0033] This invention first utilizes the dipole polarization effect of microwaves to rapidly and uniformly heat and co-melt polar monomers (lactide and glycolide) and alkaline earth metal catalysts. Simultaneously, high-frequency oscillations promote the vaporization and removal of trace amounts of bound water in the system, preventing water-induced chain transfer side reactions and providing an anhydrous environment for subsequent polymerization. The alkaline earth metal catalyst is pre-mixed with the monomers and uniformly dispersed under microwave conditions; subsequently, an amine metal catalyst is injected, forming a bimetallic synergistic catalytic system. The bulky ligands (diethylamino, N-methyl-O-ethylhydroxyamino) in the amine metal catalyst create steric hindrance, inhibiting the preferential coordination of small-molecule glycolide. Simultaneously, the electron-donating effect of the ligand heteroatoms enhances the nucleophilicity of the metal center, increasing the ring-opening rate of lactide, thereby compensating for the difference in polymerization rates between the two monomers and promoting random copolymerization. In the later stages of polymerization, the system viscosity increases. The shearing and surface renewal effects of the extruder maintain a micro-mixed state, preventing local monomer concentration imbalances that could lead to block formation and ensuring a uniform and continuous reaction.

[0034] In some preferred embodiments of the present invention, the amounts of each raw material, by weight, are: 1-150 parts of lactide, 1-150 parts of glycolide, 0.001-0.3 parts of alkaline earth metal catalyst, and 0.001-0.3 parts of amine metal catalyst. Preferably, the amounts of each raw material, by weight, are: 50-85 parts of lactide, 15-50 parts of glycolide, 0.05-0.2 parts of alkaline earth metal catalyst, and 0.01-0.2 parts of amine metal catalyst.

[0035] In some preferred embodiments of the present invention, the alkaline earth metal catalyst is magnesium lactate. Magnesium lactate has good thermal stability, excellent compatibility with lactide and glycolide, and can be uniformly dispersed in a microwave field. Magnesium ions, as Lewis acid centers, can weakly coordinate with the carbonyl oxygen of the monomer, assisting in the activation of the monomer; at the same time, the lactate group does not interfere with the subsequent initiation of the amine metal catalyst and has high biosafety.

[0036] In some preferred embodiments of the present invention, the conditions for pulsed microwave processing are: ambient pressure, microwave power of 100–300 W, temperature of 80–140 °C, and processing time of 1–5 minutes. Preferably, the microwave power is 180–280 W, the temperature is 105–135 °C, and the processing time is 2–5 minutes.

[0037] In some preferred embodiments of the present invention, the reaction conditions inside the conical twin-screw extruder are: a temperature of 140–200°C, a material residence time of 1–5 minutes, and a screw speed of 10–200 rpm. Preferably, the temperature is 155–195°C, the material residence time is 5 minutes, and the screw speed is 40–180 rpm.

[0038] In some preferred embodiments of the present invention, the lactide is selected from L-lactide, D-lactide and D,L-lactide.

[0039] In some preferred embodiments of the present invention, the polymerization reaction temperature is 175–185°C, and the reaction time is 10–20 min. The method of the present invention is carried out in an inert gas atmosphere; in some preferred embodiments of the present invention, the inert gas is nitrogen, argon, or helium.

[0040] In some preferred embodiments of the present invention, the structural formula of the amine metal catalyst is M[N(CH2CH3)2][N(CH3)(OCH2CH3)], wherein M is selected from Zn, Ca or Mg; preferably, the structural formula of the amine metal catalyst is Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)].

[0041] The present invention takes Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)] as an example, and its specific preparation method is as follows: Under an inert atmosphere, n-butyllithium (8.4 mL, 2.5 M n-hexane solution, 21.0 mmol) was slowly added dropwise to an anhydrous toluene (20 mL) solution of diethylamine (0.77 g, 10.5 mmol) and N-methyl-O-ethylhydroxylamine (0.79 g, 10.5 mmol). After the addition was complete, the reaction was continued for 1 h to obtain a mixed aminolithium solution. Subsequently, the mixture was added dropwise to an anhydrous MgCl2 (0.95 g, 10.0 mmol) suspension in toluene (30 mL). The temperature was raised to 70 °C and refluxed for 0.5 h. After the reaction was complete, the temperature was lowered to room temperature (25 ± 2 °C), filtered, and the clear filtrate was collected. The toluene solvent was removed by high vacuum distillation to obtain the amino metal catalyst Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)].

[0042] The amine-based metal catalyst used in this invention contains two different ligands: diethylamino (strong electron donor, large steric hindrance) and N-methyl-O-ethylhydroxyamino (oxygen-containing, tunable nucleophilicity). The ligands hinder the preferential approach of lactide (small molecule) to the metal center, reducing its polymerization rate. Additionally, the electron donation of the ligands increases the electron cloud density of the metal center, enhancing its nucleophilic attack ability on the carbonyl carbon of lactide and increasing the ring-opening rate of lactide. The combined effect of these two factors causes the apparent polymerization rates of LA and GA to converge, achieving random copolymerization.

[0043] In some preferred embodiments of the present invention, the method for preparing random PLGA specifically includes the following steps: 1–150 parts of lactide, 1–150 parts of glycolide, and 0.001–0.3 parts of magnesium lactate were mixed. The resulting mixture was placed in a microwave field (atmospheric pressure, microwave power of 100–300 W, temperature of 80–140 °C, and treatment time of 1–5 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 140–200 °C and the rotation speed was set to 10–200 rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.001–0.3 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes. Then, the reaction temperature was set to 175–185 °C, and the polymerization reaction was carried out for 10–20 minutes to obtain random PLGA.

[0044] In this invention, "random" refers to the random distribution of lactide (LA) and glycolide (GA) monomer units along the polymer molecular chain in polylactic acid-glycolic acid copolymer (PLGA), rather than forming a continuous block structure (i.e., avoiding long-segment polylactic acid or polyglycolic acid blocks). Traditional catalytic methods tend to generate crystalline block copolymers due to differences in monomer reactivity ratios. However, this invention, through a dual-catalytic system and reactive extrusion process, makes the apparent polymerization rates of the two monomers tend to be consistent, thereby obtaining a copolymer with a near-ideal random structure. The randomness R is calculated using carbon NMR spectroscopy; the closer the R value is to 1, the more random it is.

[0045] Unless otherwise specified, "parts" in the embodiments of this invention refer to the number of parts by weight.

[0046] All raw materials used in the embodiments of this invention were purchased commercially.

[0047] The technical solution of the present invention will be further illustrated by the following embodiments.

[0048] Example 1

[0049] 80 parts of L-lactide, 20 parts of glycolide, and 0.05 parts of magnesium lactate were mixed. The resulting mixture was placed in a microwave field (atmospheric pressure, microwave power of 180W, temperature of 105℃, and treatment time of 3 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 160℃ and the rotation speed was set to 60 rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.05 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes. Then, the reaction temperature was set to 180℃ and the polymerization reaction was carried out for 10 minutes to obtain random PLGA.

[0050] Example 2

[0051] 75 parts L-lactide, 25 parts glycolide, and 0.02 parts magnesium lactate were mixed. The resulting mixture was placed in a microwave field (atmospheric pressure, microwave power of 220W, temperature of 115℃, and treatment time of 5 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 165℃ and the rotation speed was set to 40 rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.02 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes. Then, the reaction temperature was set to 175℃, and the polymerization reaction was carried out for 15 minutes to obtain random PLGA.

[0052] Example 3

[0053] 85 parts of D,L-lactide, 15 parts of glycolide, and 0.01 parts of magnesium lactate were mixed. The resulting mixture was placed in a microwave field (at ambient pressure, microwave power of 200W, temperature of 110℃, and treatment time of 4 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 155℃ and the rotation speed was set to 80 rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.01 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes, and then the reaction temperature was set to 185℃. The polymerization reaction was carried out for 20 minutes to obtain random PLGA.

[0054] Example 4

[0055] 50 parts L-lactide, 50 parts glycolide, and 0.10 parts magnesium lactate were mixed. The resulting mixture was placed in a microwave field (at ambient pressure, microwave power of 240W, temperature of 120℃, and treatment time of 4 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 185℃ and the rotation speed was set to 120rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.10 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes. Then, the reaction temperature was set to 182℃, and the polymerization reaction was carried out for 16 minutes to obtain random PLGA.

[0056] Example 5

[0057] 60 parts of D-lactide, 40 parts of glycolide, and 0.20 parts of magnesium lactate were mixed. The resulting mixture was placed in a microwave field (atmospheric pressure, microwave power of 280W, temperature of 135℃, and treatment time of 2 minutes) for pulsed microwave treatment to melt it into a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 195℃ and the rotation speed was set to 180rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.20 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes. Then, the reaction temperature was set to 185℃, and the polymerization reaction was carried out for 18 minutes to obtain random PLGA.

[0058] Comparative Example 1 The addition of magnesium lactate is omitted, specifically: 75 parts of L-lactide and 25 parts of glycolide were mixed and placed in a microwave field (atmospheric pressure, microwave power of 220W, temperature of 115℃, and treatment time of 5 minutes) for pulsed microwave treatment to melt it into a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 165℃ and the rotation speed was set to 40 rpm. The homogeneous liquid was added to the conical twin-screw extruder, along with 0.03 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]). The mixture was kept at this temperature for 5 minutes, and then the reaction temperature was set to 170℃. The polymerization reaction was carried out for 20 minutes to obtain PLGA.

[0059] Comparative Example 2 65 parts of D,L-lactide, 35 parts of glycolide, and 0.02 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]) were added sequentially to a three-necked flask. The oil bath was heated to 175°C and maintained at a constant temperature for 30 min.

[0060] Comparative Example 3 50 parts of L-lactide, 50 parts of glycolide and 0.08 parts of magnesium lactate were mixed. The resulting mixture was placed in a microwave field (at normal pressure, microwave power of 180W, temperature of 105℃, treatment time of 3 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 160℃, the speed was set to 40rpm, and the temperature was held for 5 minutes. Then the reaction temperature was set to 180℃ and the polymerization reaction was carried out for 20 minutes.

[0061] Comparative Example 4 Under constant temperature oil bath heating conditions, 75 parts of D,L-lactide, 25 parts of glycolide, and 0.02 parts of magnesium lactate were sequentially added to a three-necked flask. The mixture was dried and dehydrated at 60°C under high vacuum (<5 mbar) for 60 min. Then, the temperature was increased to 100°C at 10°C / min to melt and mix evenly to obtain a mixture. The extruder temperature was set to 175°C and the speed was set to 40 rpm. The mixture and 0.02 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]) were added and kept at this temperature for 5 min. Then, the reaction temperature was set to 175°C and the reaction was carried out for 25 min.

[0062] Comparative Example 5 Under constant temperature oil bath heating conditions, 75 parts of D,L-lactide, 25 parts of glycolide and 0.02 parts of magnesium lactate were added sequentially to a three-necked flask. The mixture was dried and dehydrated at 60°C under high vacuum (<5mbar) for 60 min. Then, the temperature was increased to 100°C at 10°C / min to melt and mix evenly to obtain a mixture. 0.02 parts of amine metal catalyst (Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)]) was added to the mixture, and the temperature was maintained for 5 min. Then, the temperature was increased to 180°C at 10°C / min and the reaction was carried out for 120 min.

[0063] Comparative Example 6 80 parts of L-lactide, 20 parts of glycolide, and 0.05 parts of stannous octoate were mixed. The resulting mixture was placed in a microwave field (atmospheric pressure, microwave power of 180W, temperature of 105℃, and treatment time of 3 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 160℃ and the speed was set to 80rpm. The homogeneous liquid was added to the conical twin-screw extruder and kept at this temperature for 5 minutes. Then, the reaction temperature was set to 180℃ and the polymerization reaction was carried out for 60 minutes.

[0064] Comparative Example 7 80 parts L-lactide, 20 parts glycolide, 0.05 parts stannous octoate, and 0.05 parts lauryl alcohol were mixed. The resulting mixture was placed in a microwave field (at normal pressure, microwave power of 180W, temperature of 105℃, and treatment time of 3 minutes) for pulsed microwave treatment to melt it and form a homogeneous liquid. The temperature of the conical twin-screw extruder was set to 160℃ and the speed was set to 80rpm. The homogeneous liquid was added to the conical twin-screw extruder and kept at this temperature for 5 minutes. Then, the reaction temperature was set to 180℃ and the polymerization reaction was carried out for 60 minutes.

[0065] Performance testing The synthesis ratio of PLGA was obtained by NMR spectroscopy.

[0066] The randomness R can be obtained from the NMR C spectrum, and the calculation formula is: ; In the formula, I LG express 13 The integral area of ​​the characteristic peaks corresponding to adjacent sequences of LA-GA in the C NMR spectrum; I GL express 13 The integral area of ​​the characteristic peaks corresponding to adjacent sequences of GA-LA in the C NMR spectrum; I LL express 13 The integral area of ​​the characteristic peaks corresponding to adjacent LA-LA sequences in the C NMR spectrum; I GG express 13 The integral area unit of the characteristic peak corresponding to the adjacent GA-GA sequence in the C NMR spectrum. The above integral areas are all relative integral values ​​and are dimensionless.

[0067] Molecular weight data and spectra were determined using ultra-high performance gel permeation chromatography (APC).

[0068] Tensile strength and elongation at break were both determined by a universal testing machine.

[0069] Test subjects: Products obtained from Examples 1-3 and Comparative Examples 1-7.

[0070] Figure 1 The NMR C spectrum of the PLGA synthesized in Example 1 of this invention is shown.

[0071] Figure 2 The NMR spectrum of the PLGA synthesized in Example 1 of this invention shows characteristic multiplets at approximately 5.2 ppm and 4.80 ppm, belonging to the methine (-CH-) unit of lactic acid (LA) and the methylene (-CH2-) unit of glycolic acid (GA), respectively. Since the characteristic peak of lactic acid (LA) corresponds to one proton, while the characteristic peak of glycolic acid (GA) corresponds to two protons, we divided the integrated areas of their NMR spectra by 1 and 2, respectively, during calculation. This eliminates the error caused by the different proton counts, obtaining their true relative quantities in the copolymer molecular chain. After this relative molar conversion and normalization, the actual copolymer molar ratio of LA to GA in the synthesized PLGA is finally determined to be 0.79:0.21.

[0072] Figure 3 This is the molecular weight gel permeation chromatography (APC) chromatogram of PLGA synthesized in Example 1 of this invention.

[0073] The specific test results of the products obtained in Examples 1-3 and Comparative Examples 1-7 are shown in Table 1.

[0074] Table 1. Summary of data from the examples and comparative examples

[0075] Note: PDI is a key parameter in polymer science that describes the width of molecular weight distribution. It is calculated as weight-average molecular weight (Mw) / number-average molecular weight (Mn).

[0076] As shown in Table 1, the embodiments of the present invention, through the synergistic effect of microwave-dual catalysis-reactive extrusion, overcome the differences in monomer reactivity and high-viscosity mass transfer resistance, increasing the randomness of PLGA from 0.35 to 0.89-0.99 and the weight-average molecular weight from 39872 to 211657 in a short time. Benefiting from this, the tensile strength of the material is enhanced from 16.8 MPa to 78.1 MPa, and the elongation at break is toughened from 1.5% to 13.6%, with performance indicators superior to the traditional stannous octoate melt copolymerization process. In contrast, in Comparative Examples 1 and 3, due to the omission of the alkaline earth metal catalyst magnesium lactate and the amine metal catalyst, respectively, the randomness of PLGA was only 0.56 and 0.48, and the tensile strength and elongation at break also showed a significant decrease compared to the examples. This indicates that the synergistic catalytic mechanism of the two catalysts in the polymerization process compensates for the intrinsic activity differences between monomers, making the apparent polymerization rates of lactide and glycolide tend to be consistent; both are indispensable. Comparative Example 2, by omitting the alkaline earth metal catalyst magnesium lactate, adopted a one-pot polymerization reaction, resulting in the lowest randomness of the product, only 0.35, and the worst tensile strength and elongation at break. Comparative Examples 4 and 5 used vacuum drying dehydration, but the bound water was not completely removed. Comparative Examples 6 and 7 used the conventional stannous octoate melt copolymerization process, which easily generated crystalline block copolymers, making it difficult to obtain PLGA with high randomness.

[0077] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing a random PLGA, characterized in that, Includes the following steps: Lactide, glycolide and alkaline earth metal catalyst were mixed and the resulting mixture was subjected to pulsed microwave treatment to melt it into a homogeneous liquid; The homogeneous liquid is added to a conical twin-screw extruder, and an amine metal catalyst is injected into the extruder to initiate a polymerization reaction, thereby obtaining random PLGA.

2. The method for preparing random PLGA according to claim 1, characterized in that, The amounts of each raw material, by weight, are: 1-150 parts of lactide, 1-150 parts of glycolide, 0.001-0.3 parts of alkaline earth metal catalyst, and 0.001-0.3 parts of amine metal catalyst.

3. The method for preparing random PLGA according to claim 2, characterized in that, The alkaline earth metal catalyst is magnesium lactate.

4. The method for preparing random PLGA according to claim 2, characterized in that, The structural formula of the amine-based metal catalyst is M[N(CH2CH3)2][N(CH3)(OCH2CH3)], where M is selected from Zn, Ca or Mg.

5. The method for preparing random PLGA according to claim 4, characterized in that, The structural formula of the amine-based metal catalyst is Mg[N(CH2CH3)2][N(CH3)(OCH2CH3)].

6. The method for preparing random PLGA according to claim 4, characterized in that, The preparation method of the amine-based metal catalyst is as follows: Under an inert atmosphere, n-butyllithium was added dropwise to an anhydrous toluene solution of diethylamine and N-methyl-O-ethylhydroxylamine, and the mixture was allowed to react completely to obtain a mixed amino-lithium solution. Subsequently, the mixed amino-lithium solution was added dropwise to a toluene suspension of anhydrous metal chloride, and the mixture was heated under reflux. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the clear filtrate was collected. The toluene solvent was removed by high-vacuum distillation to obtain the amino-metal catalyst.

7. The method for preparing random PLGA according to claim 1, characterized in that, The polymerization reaction is carried out at a temperature of 175–185°C for a reaction time of 10–20 min.

8. The method for preparing random PLGA according to claim 1, characterized in that, The conditions for pulsed microwave processing are: ambient pressure, microwave power of 100-300W, temperature of 80-140℃, and processing time of 1-5 minutes.

9. The method for preparing random PLGA according to claim 1, characterized in that, The reaction conditions inside the conical twin-screw extruder are: temperature of 140–200℃, material residence time of 1–5 minutes, and screw speed of 10–200 rpm.

10. The method for preparing random PLGA according to claim 1, characterized in that, The lactide is selected from one of L-lactide, D-lactide, and D,L-lactide.

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