A method for controllable preparation of polyglycolide-caprolactone copolymer low-temperature prepolymer based on melting point difference

Abstract

This invention discloses a method for preparing poly(glycolic acid-caprolactone) copolymers, belonging to the field of polymer synthesis technology. The method includes: prepolymerizing ε-caprolactone with a catalyst and initiator at 40–60°C below the melting point of glycolide under an inert atmosphere; adding glycolide and heating to 160–220°C for the main polymerization reaction; after the reaction, dissolving, precipitating, washing, and drying to obtain the poly(glycolic acid-caprolactone) copolymer. This invention utilizes the physical difference in melting points between glycolide and ε-caprolactone, preferentially prepolymerizing ε-caprolactone at a temperature below the melting point of glycolide, resulting in a higher conversion rate of ε-caprolactone than glycolide in the initial stage of the main polymerization, effectively controlling the copolymerization reaction pathway. Using this method, copolymers with a weight-average molecular weight of not less than 100,000 Da and an intrinsic viscosity of 1.8–3.5 dL / g can be obtained within a wide range of glycolide molar content from 15% to 85%, and the degradation behavior is stable and controllable. This method is simple and requires no special equipment or chain extender, making it suitable for the large-scale preparation of medical materials such as absorbable sutures and tissue repair scaffolds.

Description

Technical Field

[0001] This invention belongs to the field of polymer material synthesis technology, specifically relating to a method for preparing polyglycolic acid-caprolactone copolymer (PGCL). Background Technology

[0002] Poly(glycolide-co-ε-caprolactone) copolymers (PGCLs) are an important class of biodegradable aliphatic polyester materials. Their degradation rate, mechanical properties, and flexibility can be controlled by adjusting the ratio of glycolide (GA) to ε-caprolactone (CL), thus showing broad application prospects in biomedical fields such as absorbable sutures, tissue engineering scaffolds, and drug-controlled release carriers. The overall performance of PGCL materials is influenced not only by the molar composition of GA / CL but also by the molecular weight and molecular weight distribution of the copolymer, as well as the sequence distribution of GA and CL structural units within the polymer chain.

[0003] Currently, PGCL is typically prepared by melt ring-opening copolymerization using metal catalysts (such as stannous octoate). However, due to the significant difference in reactivity between GA and CL monomers, a mismatch exists in their polymerization reactivity ratios (r). GA >1, r CL <1), In the conventional synchronous feeding melt bulk copolymerization process, problems such as uncoordinated monomer consumption rate, uneven distribution of chain segment sequence and molecular weight fluctuation are prone to occur, which affects the predictability of material performance control.

[0004] To address the aforementioned issues, existing technologies have proposed various improvement strategies.

[0005] For example, one type of method controls the chain segment structure through stepwise polymerization or sequential addition. Patent CN106986984A discloses a two-step method for preparing PGCL copolymers, which first initiates CL polymerization and then adds GA for subsequent polymerization. This method improves the chain structure to some extent by changing the order of monomer addition, but its reaction temperature range is relatively wide, and the stability and controllability of the polymerization process may still be limited under different GA content systems.

[0006] Another approach involves introducing a third monomer (such as lactide, LA) to form a ternary copolymer system, combined with stepwise addition to improve material processing performance or meet melt spinning requirements. For example, patent CN1211582A discloses a two-step polymerization method for lactide / caprolactone / glycolide (LA / CL / GA) ternary copolymers; patent CN113881021A discloses a stepwise polymerization process for glycolide / lactide / caprolactone (GA / LA / CL) ternary copolymers, obtaining copolymer materials suitable for spinning by adding GA in stages. While these methods can improve material properties or processing applicability to some extent, the complex system composition and the inherent reactivity differences between GA and CL still exist, potentially leading to problems such as reaction rate mismatch and difficulty in stably controlling molecular weight and sequence structure during polymerization.

[0007] In addition, some researchers have attempted to increase the molecular weight of the product by introducing external energy (such as ultrasound or microwave) or subsequent chain extension methods. For example, patent CN110028655A uses ultrasound-assisted melt ring-opening polymerization; patent CN112920384B uses microwave segmented heating and batch addition of GA; and patent CN117186367A adds a chain extender after polymerization to increase the molecular weight. Such methods can improve polymerization efficiency or increase molecular weight to some extent, but they usually rely on specialized equipment or introduce additional process steps, and their main polymerization stage still takes place in the molten state where GA and CL react simultaneously, making it difficult to effectively control the competitive reaction behavior of monomers from the initial stage of polymerization.

[0008] Other researchers employ prepolymerization methods to achieve continuous polyester production using continuous flow reactors or twin-screw extruders. For example, patent CN114161682A discloses a method for preparing medical absorbable polyester using supercritical fluid-assisted twin-screw continuous extrusion. This method involves prepolymerization at a higher temperature, allowing GA and CL to melt and react simultaneously to obtain a prepolymer, which is then polymerized through subsequent processes. While this type of method enables continuous production, its prepolymerization temperature is typically higher than the melting point of GA. At this temperature, both GA and CL are in a molten state and simultaneously participate in the ring-opening reaction, making it difficult to specifically control the reaction pathway at the beginning of polymerization by utilizing the difference in the physical states of GA and CL.

[0009] For example, patent CN118146490A discloses a method for the continuous and efficient preparation of high molecular weight polyester materials. This method involves prepolymerization in a reactor followed by monomer addition via a twin-screw extruder for continued polymerization. While this method also employs a "prepolymerization + monomer addition" process, its prepolymerization temperature is 120-180℃, which is higher than the melting point of glycolide (approximately 85℃). Both glycolide and caprolactone are in a molten state and participate in the ring-opening reaction simultaneously, making it impossible to specifically control the reaction pathway at the beginning of polymerization by utilizing the difference in their physical states. In contrast, this invention controls the prepolymerization temperature below the melting point of glycolide, leveraging the difference in physical properties—glycolic acid is solid and caprolactone is liquid—to achieve preferential ring-opening of caprolactone.

[0010] In summary, while existing technologies have proposed improvements such as stepwise polymerization, the introduction of a third monomer, external energy-assisted polymerization, chain extension, and continuous flow prepolymerization, these methods typically enter the main polymerization stage after both GA and CL are in a molten state. This fails to fully utilize the physical difference between GA's high melting point (approximately 85°C) and CL's liquid state at lower temperatures, and to establish a reaction environment favorable for preferential ring-opening and chain growth of CL under GA-unmelted conditions. Therefore, there is still an urgent need to develop a method for preparing PGCL applicable to a wide range of GA contents, to achieve stable preparation of high molecular weight PGCL copolymers without the need for special equipment or chain extension steps, and to further improve the controllability of the copolymer chain sequence structure and the predictability of degradation performance. Summary of the Invention

[0011] This invention provides a controllable preparation method for poly(glycolide-caprolactone) copolymers (PGCL) applicable to a wide range of GA content. The core of the method lies in utilizing the physical difference between glycolide (GA) with its high melting point (approximately 85°C) and ε-caprolactone (CL) which is liquid at lower temperatures. CL is prepolymerized at 40–60°C, below the melting point of glycolide, allowing CL to preferentially open rings and form an active chain growth environment (GA is solid and does not participate in the reaction). The main polymerization reaction then proceeds at 160–220°C. This allows for effective control of the copolymerization reaction pathway between GA and CL without the need for special equipment or chain extenders, resulting in the stable preparation of high molecular weight PGCL copolymers with more uniform sequence distribution and more controllable degradation behavior.

[0012] The method of this invention is applicable to a wide range of copolymerization systems with GA molar content of 15–85 mol%, and can maintain the stability of the polymerization process under different composition conditions, obtaining PGCL products with high intrinsic viscosity and high molecular weight. The repeating structural unit of PGCL is as follows:

[0013] The present invention adopts the following technical solution: This invention provides a method for preparing a poly(glycolide-caprolactone) copolymer with a wide range of compositions, comprising the following steps: (1) Under an inert atmosphere, ε-caprolactone monomer, catalyst and initiator are added to the reactor and a prepolymerization reaction is carried out at 40-60°C below the melting point of glycolide for 20-40 minutes. (2) Add glycolide monomer to the prepolymer system of step (1), and then heat the reaction system to 160-220℃ for main polymerization reaction. Based on the molar content X of GA structural unit in the target copolymer, the stirring program and reaction time of the main polymerization stage are differentiated by section. (3) After the reaction is completed, the product is dissolved, precipitated, washed and dried to obtain the polyglycolic acid-caprolactone copolymer.

[0014] The molar content X of the GA structural unit satisfies: X = x / (x+y) × 100%, and X is 15% to 85%.

[0015] Preferably, the stirring program and reaction time of the main polymerization stage are differentially controlled in different sections based on the molar content X of GA in the target copolymer: a) When X is 15–30 mol%, the stirring speed is 50–300 rpm, and the reaction time is 1.5–2.5 hours; b) When X is 40–60 mol%, a segmented control method is adopted to gradually reduce the stirring speed as the reaction progresses: 0–30 minutes after adding GA, the stirring speed is 150–300 rpm; 30–90 minutes, the stirring speed is 80–150 rpm; after 90 minutes, the stirring speed is 30–80 rpm; the total reaction time is 1–2 hours. c) When X is 70–85 mol%, the stirring speed is 50–300 rpm and the reaction time is 0.25–1 hour.

[0016] Preferably, the catalyst is a tin-based catalyst, selected from at least one of stannous octoate, stannous isooctanoate, stannous oxalate, and stannous chloride; the initiator is a C1-C12 alkanol, selected from at least one of benzyl alcohol, butanol, and dodecanol.

[0017] More preferably, the amount of catalyst used is 0.01 to 0.05 wt% of the total mass of CL and GA monomers, and the amount of initiator used is 0.05 to 0.15 mol% of the total molar mass of CL and GA monomers.

[0018] Compared with the prior art, the present invention has the following advantages and technical effects: 1) Effective control of the reaction pathway in the initial stage of polymerization was achieved. This invention utilizes the melting point difference between GA and CL (GA melting point 85℃, CL melting point -1℃) to perform prepolymerization at a temperature 40–60℃ below the melting point of GA. At this temperature, CL is liquid and GA is solid, causing CL to preferentially undergo ring-opening, while GA does not participate in the reaction. Compared with existing technologies (such as CN118146490A) where the prepolymerization temperature is higher than the melting point of GA, this invention achieves preferential chain growth of CL in a solid-liquid heterogeneous system for the first time, successfully reversing the traditional reaction order determined by the reactivity ratio (r). GA >r CL Kinetic monitoring results showed that in the early stage of the main polymerization, the CL conversion rate was significantly higher than that of GA (as shown in Table 2), which promoted the formation of PGCL copolymers with a more uniform sequence distribution.

[0019] 2) Stable preparation of high molecular weight PGCL copolymers over a wide compositional range This invention, through the synergistic effect of a low-temperature prepolymerization step and a segmented stirring strategy, can adapt to viscosity changes during polymerization of systems with different GA contents, improving mass transfer and mixing effects. This allows for the stable preparation of PGCL copolymers with intrinsic viscosities not lower than 1.8 dL / g over a wide GA content range of 15–85 mol%, with a maximum intrinsic viscosity reaching 3.5 dL / g; the resulting copolymer M w Not less than 100,000 Da, and up to 210,353 Da, with a polydispersity index (PDI) ≤ 1.82.

[0020] 3) The degradation behavior is more stable and more predictable. In vitro degradation experiments showed that, under PBS buffer (pH=7.4) and 37°C conditions, the PGCL copolymer prepared by the method of this invention exhibited a slower and more stable mass loss process compared to the traditional one-pot method product, with a significantly reduced degradation rate. This improved the long-term support capacity and performance predictability of the material in applications such as absorbable sutures and tissue engineering.

[0021] 4) The process is simple, requires low-level equipment, and is suitable for scale-up. The method of this invention does not require special equipment such as ultrasound or microwave, nor does it require chain extenders or complex subsequent reactions. It can be achieved simply by coordinating the temperature and stirring programs. The process is simple, highly stable, and suitable for large-scale preparation. Attached Figure Description

[0022] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly described below. Obviously, the drawings described below are merely some embodiments of the present invention. Those skilled in the art can obtain other information from these drawings without any creative effort.

[0023] Figure 1 The ¹H NMR spectrum of the poly(glycolic acid)-caprolactone copolymer (PGCL) obtained in Example 4 is shown below. Figure 2 The attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum of the poly(glycolide-caprolactone) copolymer (PGCL) obtained in Example 4 is shown below. Figure 3 The image shows the gel permeation chromatography (APC / GPC) chromatogram of the poly(glycolic acid-caprolactone) copolymer (PGCL) obtained in Example 4. Detailed Implementation

[0024] In the embodiments of the present invention, unless otherwise specified, the polymerization reaction is carried out in a 500 mL three-necked flask equipped with a mechanical stirrer, thermometer and inert gas protection device, and the temperature is controlled by oil bath heating.

[0025] The catalyst is selected from tin-based catalysts, such as stannous octoate, stannous isooctanoate, stannous oxalate, or stannous chloride; the initiator is selected from C1-C12 alkanols, such as benzyl alcohol, butanol, or dodecanol. The catalyst and initiator are pre-dissolved in purified toluene to prepare a homogeneous solution before use. In the following examples, unless otherwise specified, the amount of stannous octoate catalyst is 0.02 wt% of the total mass of ε-caprolactone (CL) and glycolide (GA) monomers, and the amount of benzyl alcohol initiator is 0.075 mol% of the total molar mass of the monomers. These examples can be adjusted within the stated range; see the examples for details.

[0026] After the polymerization reaction was completed, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was then slowly poured into an excess of ice-cold ethanol with stirring to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent (volume ratio 1:1), and dried under vacuum at 40°C for 24 hours to obtain the PGCL copolymer.

[0027] [Example 1] A copolymerization system with a GA / CL molar ratio of 15:85 was used. 162.0 mL (1.42 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.01 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.15 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 60°C (below the melting point of glycolide) for prepolymerization, stirred at 150 rpm for 30 minutes. Subsequently, 30.00 g (0.26 mol) of glycolide was added to the reaction system, and the system was heated to 180°C for the main polymerization reaction, maintained at 150 rpm for 2.0 hours.

[0028] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0029] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 14.98:85.02. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity [η] was 133,861 dL, with a polydispersity index (PDI) of 1.61. The intrinsic viscosity [η], measured at 25 °C with HFIP as the solvent at a concentration of 0.4 g / dL, was 3.52 dL / g. The yield was 81.6%.

[0030] [Example 2] A copolymerization system with a GA / CL molar ratio of 30:70 was used. 138.0 mL (1.21 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.02 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.15 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 60°C (below the melting point of glycolide) for prepolymerization, stirred at 150 rpm for 30 minutes. Subsequently, 61.98 g (0.53 mol) of glycolide was added to the reaction system, and the system was heated to 160°C for the main polymerization reaction, maintained at 150 rpm for 1.5 hours.

[0031] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0032] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 31.06:68.94. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity (η) was 112,945 Da, and the polydispersity index (PDI) was 1.74. The intrinsic viscosity [η], measured at 25 °C with HFIP as the solvent at a concentration of 0.4 g / dL, was 2.46 dL / g. The yield was 84.2%.

[0033] [Example 3] A copolymerization system with a GA / CL molar ratio of 40:60 was used. 113.0 mL (0.99 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.02 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.10 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 60°C, below the melting point of glycolide, for prepolymerization, and stirred at 150 rpm for 30 minutes. Subsequently, 79.15 g (0.68 mol) of glycolide was added to the reaction system, and the system was heated to 190 °C to carry out the main polymerization reaction. A strategy of reducing the stirring speed in stages was adopted: 150 rpm for 0-20 minutes after adding GA; 100 rpm for 20-40 minutes; and 50 rpm after 40 minutes. The total reaction time was 1 hour.

[0034] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0035] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 39.68:60.32. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity (η) was 112,347 dL / g, with a polydispersity index (PDI) of 1.64. The intrinsic viscosity [η], measured at 25 °C with HFIP as the solvent at a concentration of 0.4 g / dL, was 2.42 dL / g. The yield was 83.7%.

[0036] [Example 4] A copolymerization system with a GA / CL molar ratio of 50:50 was used. 95.0 mL (0.83 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.03 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.075 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 50°C below the melting point of glycolide for prepolymerization, and stirred at 150 rpm for 30 minutes.

[0037] Subsequently, 98.90 g (0.85 mol) of glycolide was added to the reaction system, and the system was heated to 180 °C for the main polymerization reaction. The following staged reduction strategy of stirring speed was adopted: 0-30 minutes after the addition of GA, the stirring speed was 300 rpm; 30-90 minutes, the stirring speed was reduced to 150 rpm; after 90 minutes, the stirring speed was reduced to 50 rpm. The total reaction time was 2 hours.

[0038] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0039] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 48.78:51.22. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity [η] was 124,299 Da, and the polydispersity index (PDI) was 1.57. The intrinsic viscosity [η], measured at 25°C with HFIP as the solvent and a concentration of 0.4 g / dL, was 2.08 dL / g. The yield was 85.4%.

[0040] [Example 5] A copolymerization system with a GA / CL molar ratio of 60:40 was used. 76.0 mL (0.67 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.04 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.075 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 60°C, below the melting point of glycolide, for prepolymerization, and stirred at 150 rpm for 30 minutes.

[0041] Subsequently, 120.22 g (1.03 mol) of glycolide was added to the reaction system, and the system was heated to 200 °C to carry out the main polymerization reaction. A strategy of reducing the stirring speed in stages was adopted: the stirring speed was 200 rpm for 0-20 minutes after the addition of GA; the stirring speed was 100 rpm for 20-40 minutes; and the stirring speed was 50 rpm after 40 minutes. The total reaction time was 1 hour.

[0042] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0043] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 57.47:42.53. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity (η) was 144,618 Da, and the polydispersity index (PDI) was 1.73. The intrinsic viscosity [η], measured at 25 °C with HFIP as the solvent at a concentration of 0.4 g / dL, was 1.88 dL / g. The yield was 79.5%.

[0044] [Example 6] A copolymerization system with a GA / CL molar ratio of 70:30 was used. 57.0 mL (0.50 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.04 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.05 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 50°C below the melting point of glycolide for prepolymerization, and stirred at 150 rpm for 30 minutes.

[0045] Subsequently, 139.00 g (1.20 mol) of glycolide was added to the reaction system, and the system was heated to 210 °C to carry out the main polymerization reaction. The stirring speed was kept at 150 rpm, and the reaction was carried out for 0.75 hours.

[0046] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0047] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 72.46:27.54. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity [η] was 147,008 dL, with a polydispersity index (PDI) of 1.76. The intrinsic viscosity [η], measured at 25 °C with HFIP as the solvent at a concentration of 0.4 g / dL, was 1.89 dL / g. The yield was 82.3%.

[0048] [Example 7] A copolymerization system with a GA / CL molar ratio of 85:15 was used. 28.0 mL (0.25 mol) of ε-caprolactone was added to the reactor, followed by the catalyst stannous octoate (0.05 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and the initiator benzyl alcohol (0.05 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the system was heated to 40°C below the melting point of glycolide for prepolymerization, stirred at 150 rpm for 30 minutes. Subsequently, 167.89 g (1.45 mol) of glycolide was added to the reaction system, and the system was heated to 220°C for the main polymerization reaction, maintained at 150 rpm for 0.25 hours.

[0049] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0050] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 83.50:16.50. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity [η] was 210,353 Da, and the polydispersity index (PDI) was 1.82. Measured at 25°C with HFIP as the solvent at a concentration of 0.4 g / dL, the intrinsic viscosity [η] was 2.24 dL / g. The yield was 81.1%.

[0051] [Comparative Example 1] A copolymerization system with a GA / CL molar ratio of 50:50 was used. 95.0 mL (0.85 mol) of ε-caprolactone and 98.67 g (0.85 mol) of glycolide were added to the reactor, followed by the addition of stannous octoate catalyst (0.03 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and benzyl alcohol initiator (0.075 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the reaction system was heated to 180 °C and reacted at 100 rpm for 2 hours.

[0052] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0053] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 49.12:50.88. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity (η) was 41,428 dL, with a polydispersity index (PDI) of 1.31. The intrinsic viscosity [η], measured at 25 °C with HFIP as the solvent at a concentration of 0.4 g / dL, was 0.83 dL / g. The yield was 78.3%.

[0054] [Comparative Example 2] A copolymerization system with a GA / CL molar ratio of 50:50 was used. 95.0 mL (0.85 mol) of ε-caprolactone and 98.66 g (0.85 mol) of glycolide were added to the reactor, followed by the addition of stannous octoate catalyst (0.03 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and benzyl alcohol initiator (0.075 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the reaction system was heated to 200 °C and reacted at 100 rpm for 2 hours.

[0055] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0056] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 47.34:52.66. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity (η) was 36,283 Da, and the polydispersity index (PDI) was 1.69. The intrinsic viscosity [η], measured at 25°C with HFIP as the solvent at a concentration of 0.4 g / dL, was 0.73 dL / g. The yield was 81.6%.

[0057] [Comparative Example 3] A copolymerization system with a GA / CL molar ratio of 50:50 was used. 95.0 mL (0.85 mol) of ε-caprolactone and 98.67 g (0.85 mol) of glycolide were added to the reactor, followed by the addition of stannous octoate catalyst (0.03 wt% relative to the total mass of glycolide and ε-caprolactone monomers) and benzyl alcohol initiator (0.05 mol% relative to the total molar mass of glycolide and ε-caprolactone monomers). Under an inert atmosphere, the reaction system was heated to 220 °C and reacted at 100 rpm for 2 hours.

[0058] After the reaction was complete, the system was cooled to below 80°C, and dichloromethane was added to completely dissolve the product. The polymer solution was slowly poured into excess ice-cold ethanol to precipitate the product. The solid was collected by filtration, washed twice with a dichloromethane-ethanol mixed solvent, and dried under vacuum at 40°C for 24 h to obtain the PGCL copolymer.

[0059] The obtained product was characterized. ¹H NMR analysis showed that the molar ratio of GA to CL structural units in the copolymer chain was 48.75:51.25. ATR-FTIR spectra showed characteristic absorption peaks of the ester carbonyl group. The weight-average molecular weight (M) was determined using APC. w The intrinsic viscosity (η) was 32,023 Da, and the polydispersity index (PDI) was 1.54. The intrinsic viscosity [η], measured at 25°C with HFIP as the solvent at a concentration of 0.4 g / dL, was 0.64 dL / g. The yield was 79.4%.

[0060] To verify the regulatory effect of the method of the present invention on the reaction pathway, the main polymerization process of Example 4 (the method of the present invention) and Comparative Example 1 (conventional one-pot method) was monitored. Timing began when the glycolide was completely added and the system reached its predetermined main polymerization temperature (180℃ and 200℃, respectively). Every 15 minutes, a small amount of reactant was taken out using a preheated syringe, quickly placed in ice water to cool and terminate the reaction, and then dissolved in deuterated chloroform (CDCl3) for ¹H NMR analysis, or precipitated, dried, and used for intrinsic viscosity determination. The instantaneous conversion rates of GA and CL monomers measured by ¹H NMR are listed in Table 1, and the intrinsic viscosity changes with reaction time are listed in Table 2.

[0061] Table 1. Monomer conversion rate over time (GA content 50 mol%)

[0062] Table 2. Intrinsic viscosity as a function of reaction time (GA content 50 mol%)

[0063] As shown in Table 1, in the method of this invention, the conversion rate of CL is significantly higher than that of GA in the initial stage of the main polymerization (e.g., the first 30 minutes), while in Comparative Example 1, the conversion rate of GA is consistently higher than that of CL. This indicates that the present invention effectively alters the competitive reaction behavior of the two monomers through a low-temperature prepolymerization step.

[0064] As shown in Table 2, the intrinsic viscosity growth rate of the method of the present invention (Example 4) is significantly faster than that of the one-pot method (Comparative Example 1), and the final intrinsic viscosity is higher, indicating that the method of the present invention is more conducive to the rapid and stable growth of molecular chains.

[0065] To evaluate the degradation performance of the products, approximately 4.0 g of the purified polymer samples from Example 4 and Comparative Example 1 were accurately weighed and placed in Erlenmeyer flasks containing 40 mL of phosphate-buffered saline (PBS) at pH 7.4, and allowed to degrade at a constant temperature of 37°C. Samples were taken on days 7, 14, 21, 28, 35, 42, 49, 56, and 63 of degradation. After rinsing with deionized water and vacuum drying to constant weight, the mass retention rate was calculated, and the results are listed in Table 3.

[0066] Table 3. Degradation data in PBS buffer at 37°C and pH 7.4 (GA content 50 mol%)

[0067] As shown in Table 3, the product of the present invention exhibits a more gradual mass loss during the 63-day degradation period, while the product of Comparative Example 1 shows rapid mass loss in the early stage, proving that the product of the present invention has superior and more controllable degradation performance.

[0068] 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 poly(glycolic acid-caprolactone) copolymer, characterized in that, Includes the following steps: (1) Under an inert atmosphere, ε-caprolactone monomer, catalyst and initiator are added to the reactor and prepolymerized at 40-60°C below the melting point of glycolide for 20-40 minutes. (2) Add glycolide monomer to the prepolymer system of step (1), and then heat the reaction system to 160-220℃ to carry out the main polymerization reaction; (3) After the reaction is complete, the product is dissolved, precipitated, washed and dried to obtain the polyglycolic acid-caprolactone copolymer; Wherein, the molar content X of the glycolide structural unit in the copolymer is 15-85 mol.

2. The preparation method according to claim 1, characterized in that, In step (2), the stirring program and reaction time of the main polymerization stage are differentiated by section based on the molar content X of glycolide in the target copolymer.

3. The preparation method according to claim 2, characterized in that, When X is 15–30 mol%, the stirring speed of the main polymerization reaction is 50–300 rpm, and the reaction time is 1.5–2.5 h.

4. The preparation method according to claim 2, characterized in that, When X is 40–60 mol%, the main polymerization reaction adopts a segmented control method of gradually reducing the stirring speed as the reaction progresses: after adding glycolide, the stirring speed is 150–300 rpm for 0–30 min, 80–150 rpm for 30–90 min, and 30–80 rpm after 90 min, with a total reaction time of 1–2 h.

5. The preparation method according to claim 2, characterized in that, When X is 70–85 mol%, the stirring speed of the main polymerization reaction is 50–300 rpm, and the reaction time is 0.25–1 h.

6. The preparation method according to claim 1, characterized in that, The catalyst is a tin-based catalyst, selected from at least one of stannous octoate, stannous isooctanoate, stannous oxalate, and stannous chloride; the initiator is a C1-C12 alkanol, selected from at least one of benzyl alcohol, butanol, and dodecanol.

7. The preparation method according to claim 1, characterized in that, The amount of catalyst used is 0.01 to 0.05 wt% of the total mass of ε-caprolactone and glycolide monomer, and the amount of initiator used is 0.05 to 0.15 mol% of the total molar mass of ε-caprolactone and glycolide monomer.

8. The preparation method according to claim 1, characterized in that, The dissolution in step (3) uses dichloromethane as a solvent, and the precipitation uses ethanol or methanol as a precipitant.

9. A polyglycolic acid-caprolactone copolymer, characterized in that, It is prepared by the method described in any one of claims 1 to 8.

10. The polyglycolic acid-caprolactone copolymer according to claim 9, characterized in that, The copolymer has an intrinsic viscosity [η] of 1.8 to 3.5 dL / g, a weight-average molecular weight of not less than 100,000 Da, and a polydispersity index (PDI) of not more than 1.82, measured at 25°C with hexafluoroisopropanol as solvent and a concentration of 0.4 g / dL.

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