Novel preparation method of high molecular weight and high conversion rate PLGA (poly (lactic-co-glycolic acid))

Abstract

The invention discloses a preparation method of a high molecular weight polylactic acid-glycolic acid copolymer (PLGA). According to the method, PLGA (poly (lactic-co-glycolic acid)) with relatively low molecular weight is taken as a macromolecular initiator, and ring-opening polymerization of glycolide and lactide monomers is initiated under the action of a catalyst. In the preparation process, a programmed cooling control strategy is introduced by combining the kinetic characteristics of the polymerization reaction, so that the temperature field gradient in the reaction process is accurately regulated and controlled. The control strategy effectively inhibits chain termination and thermal degradation side reactions in the later stage of the reaction while ensuring rapid proceeding of the reaction in the initial stage. According to the method disclosed by the invention, the monomer conversion rate is remarkably improved, and the ultra-high molecular weight PLGA material with the intrinsic viscosity of 1.5 or above is successfully prepared.

Description

Technical Field

[0001] This invention belongs to the field of polymer preparation technology, and more specifically, relates to a method for preparing a high molecular weight, high conversion rate PLGA copolymer. Background Technology

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

[0003] In the prior art, a patent from Central South University (CN 106432699 A) discloses an industrial production process for injectable PLGA, which utilizes 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 around 0.5 dL / g. Currently, high-temperature polymerization is generally used, which leaves a large amount of monomer residue. After the reaction, solvent washing is used to remove the monomer. A patent from Nanjing Weier Pharmaceutical Co., Ltd. (CN114920919 B) discloses a method for preparing a crude product through high-temperature polymerization, combined with multiple "dissolution-co-precipitation" and drying spray processes to remove residual monomers and solvents. Shandong Guyuchun's patent (CN 115386070 B) proposes a preparation process that synthesizes a weight-average molecular weight of 43941 under a pressure environment of 0.2-0.5 MPa, combined with a specific gradient temperature program (100-110℃ prepolymerization, 170-180℃ polymerization) and a diluted catalyst system.

[0004] Existing polymerization processes for poly(lactic-co-glycolic acid) (PLGA) have significant limitations in terms of controlling reaction conditions and balancing product properties. On the one hand, there is an inherent conflict between reaction temperature and polymerization rate, as well as molecular weight stability: if high-temperature reactions are used to improve efficiency, PLGA is highly susceptible to severe thermal degradation of its macromolecular chains due to heat sensitivity, leading to a decrease in molecular weight, a wider molecular weight distribution, and compromised quality stability. Conversely, switching to low-temperature reactions to protect the molecular chains results in a significant decrease in polymerization kinetics and a lengthy reaction cycle, severely hindering the economic efficiency of industrial production. On the other hand, to balance reaction rates, traditional processes often force a substantial increase in the amount of tin-based catalysts added. This directly results in residual tin in the finished product far exceeding the stringent limits for pharmaceutical excipients in current pharmacopoeias, limiting its application in high-end formulations. Furthermore, current synthesis processes are overly dependent on reaction time, lack precise kinetic control methods, and generally suffer from low monomer conversion rates, high monomer residues, difficulty in effectively increasing the molecular weight of the finished product, and low batch-to-batch yields. Therefore, there is an urgent need in this field to develop a PLGA synthesis method that can ensure high monomer conversion rate and high molecular weight, strictly control heavy metal residues, and have high product quality stability. Summary of the Invention

[0005] To overcome the problem of existing PLGA synthesis technologies being unable to obtain high molecular weight, high-conversion PLGA through direct polymerization, this invention employs high molecular weight PLGA as a macromolecular initiator to induce efficient ring-opening polymerization of high-purity lactide and glycolide monomers. The core of this method lies in combining the polymerization reaction kinetics with a programmed cooling control strategy. This ensures rapid reaction in the initial stage while effectively suppressing later chain termination and thermal degradation side reactions. By precisely controlling the temperature gradient during the reaction process, this invention not only achieves a higher order of magnitude increase in molecular weight, significantly improves monomer conversion, and reduces monomer residue, but also ensures that the obtained PLGA product possesses excellent quality stability and pharmaceutical compliance. To achieve the above objectives, this invention adopts the following technical solution: S1 uses PLGA particles with a weight-average molecular weight of 100,000-150,000 as an initiator, and melts and holds them at a constant temperature under an inert gas protection. S2 adds a catalyst and an initiator to the reaction system to obtain a blend; S3 adds a certain proportion of glycolide and lactide to the reactor and uses a programmed stage cooling method to conduct copolymerization experiments, producing PLGA with a weight average molecular weight of 150,000-250,000.

[0006] Furthermore, by weight, the amounts of each raw material are as follows: 100 parts PLGA initiator, 1-150 parts glycolide monomer, 1-150 parts lactide monomer, 0.001-0.3 parts catalyst, and 0.1-10 parts dispersant.

[0007] Furthermore, the ratio of LA segment to GA segment in the PLGA initiator is (10:90-90:10), the purity of glycolide and lactide is ≥99.9%, the acid content of glycolide and lactide is ≤1000ppm, and the water content is ≤1000ppm.

[0008] Furthermore, the lactide is L-lactide, D-lactide, or D,L-lactide.

[0009] Further, the catalyst is selected from one or more of stannous octoate, stannous chloride, stannous oxalate, stannous acetate, zinc lactate, zinc bromide, aluminum isopropoxide, and aluminum chloride. Preferably, the catalyst is selected from stannous octoate, stannous acetate, stannous chloride, and dibutyltin oxide. The dispersant is selected from one or more of toluene, dimethyl carbonate, cyclohexane, isopropanol, ethyl acetate, dichloromethane, and chloroform. Preferably, the dispersant is selected from toluene, cyclohexane, dichloromethane, and ethyl acetate.

[0010] Furthermore, the melting and heat preservation temperature is 180-200℃, and the heat preservation time is 2-15 minutes.

[0011] Furthermore, the programmed cooling reaction includes a first temperature stage, a second temperature stage, and a third temperature stage proceeding sequentially. The holding times for the first and second stages are strictly controlled by the pseudo-first-order open-loop kinetic equation of this system: The third stage is controlled by the peak torque. The first temperature stage involves polymerization at 180-200℃, with the reaction time sufficient for a glycolide monomer conversion exceeding 70%-90%. The second temperature stage involves polymerization at 160-180℃, with the reaction time sufficient for a lactide conversion exceeding 70%-90%. The third stage involves polymerization at 140-160℃, with the torque change rate during reaction time approaching 0-0.1.

[0012] Furthermore, the aforementioned kinetic equations are all derived from the conversion rates of each monomer at specific temperatures. .

[0013] Furthermore, the conversion rates were all obtained from 1H NMR spectroscopy.

[0014] Furthermore, S1-S3 are all carried out in a twin-cone screw extruder, and the stirring speed of the twin-cone screw extruder is 10-200 rpm.

[0015] Furthermore, the torque change rate can be determined from the twin cone screw extruder.

[0016] Furthermore, the PLGA particles have a diameter of 1-10 mm and a length of 1-20 mm.

[0017] Furthermore, steps S1-S3 are all performed under the protection of an inert gas, which is nitrogen, argon, or helium.

[0018] In this invention, PLGA particles with a weight-average molecular weight of 100,000-150,000 are used as macromolecular initiators. The mechanism by which they initiate the ring-opening polymerization of PLGA is as follows: In S1, the PLGA particles are melted and held at 180-200°C to allow the terminal groups of the polymer chain to acquire sufficient mobility and reactivity. In S2, the catalyst added (such as organometallic compounds like stannous octoate) coordinates or reacts with the hydroxyl or carboxyl groups at the terminal of the PLGA chain to form an active metal-alkoxy bond (M-OR) species, which becomes the actual ring-opening initiation center. In S3, when the glycolide and lactide monomers are added, the carbonyl carbon in its cyclic structure is subjected to nucleophilic attack by the aforementioned active metal-alkoxy bond, causing the ester bond of glycolide and lactide to break, the ring to be opened, and the newly generated oxygen anion rapidly combines with the catalyst metal center to form a new active end, while the original PLGA chain becomes part of the growth chain. This process is repeated, and glycolide and lactide monomers are continuously inserted into the active chain end of the PLGA, realizing chain extension and gradual accumulation of molecular weight. Because the reaction rates and apparent reaction rates of glycolide and lactide are different, the conversion rate of glycolide is greater than that of lactide. Furthermore, the addition of glycolide accelerates the conversion of lactide. In the first stage of the temperature-programmed cooling process, the extremely high monomer concentration and its kinetic advantage rapidly consume GA and synergistically promote LA ring-opening. At this stage, the kinetic advantage is greater than that of thermal degradation, which is beneficial for chain segment growth. After the second stage of cooling, most of the lactide in the reaction system is consumed, and the viscosity of the system increases. The final monomer is consumed at low temperature, thus synthesizing high molecular weight, high-conversion PLGA.

[0019] More specifically, the present invention provides a method for preparing high molecular weight, high conversion PLGA by melt repolymerization, comprising the following steps: S1 first sets the temperature of all areas inside the twin-cone screw extruder to 180-200℃ through the heating program, and at the same time, it creates a nitrogen environment inside by displacement. The speed of the twin-cone screw extruder is set to 10-200 rpm. Polyglycolic acid particles with a weight average molecular weight of 100,000-150,000 are added to the twin-cone screw extruder as initiators and kept at this temperature for 2-20 minutes. S2 disperses the catalyst in a dispersant, then adds it to a twin-screw extruder and circulates it with the molten PLGA initiator to obtain a mixture; S3 continues to add glycolide and lactide monomers to the twin-cone screw extruder, adjusting the equipment temperature to 180-200℃ and maintaining it for 5-20 minutes. The reaction proceeds at 180-200℃ until the glycolide conversion exceeds 70-90%. The reaction continues at 160-180℃ until the lactide conversion exceeds 70-90%, and at 140-160℃ until the torque change rate of the upper twin screw is less than 0.1%, yielding PLGA with a weight-average molecular weight (Mw) of 150,000-250,000.

[0020] Compared with the prior art, the present invention has the following advantages and technical effects: (1) In this invention, PLGA with a lower molecular weight is used as an initiator to further initiate the ring-opening polymerization of glycolide and lactide under the action of a catalyst, thereby obtaining PLGA with a higher molecular weight. The PLGA obtained has a higher intrinsic viscosity, which can reach more than 1.5. (2) The core of this invention lies in combining the kinetic characteristics of polymerization reactions and introducing a programmed cooling control strategy, which effectively suppresses chain termination and thermal degradation side reactions in the later stages while ensuring rapid reaction in the initial stage. By precisely controlling the temperature field gradient in the reaction process, this invention not only achieves a higher order of magnitude of molecular weight growth, but also significantly improves monomer conversion rate. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 The 1H NMR spectrum of the PLGA synthesized in Example 1 of this invention.

[0023] Figure 2 The kinetic data at 170°C provided for this invention.

[0024] Figure 3 The molecular weight gel permeation chromatography (APC) chromatogram of PLGA synthesized in Example 1 of this invention. Detailed Implementation

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] This invention provides a method for preparing high molecular weight, high conversion PLGA, comprising the following steps: S1 uses PLGA particles with a weight-average molecular weight of 100,000-150,000 as an initiator, and melts and holds them at a constant temperature under an inert gas protection. S2 adds a catalyst and an initiator to the reaction system to obtain a blend; S3 adds a certain proportion of glycolide and lactide to the reactor and uses a programmed stage cooling method to conduct copolymerization experiments, producing PLGA with a weight average molecular weight of 150,000-250,000.

[0031] In a preferred embodiment of the present invention, the amounts of each raw material, by weight, are as follows: 100 parts of polyglycolic acid initiator, 1-150 parts of glycolide monomer, 1-150 parts of lactide monomer, 0.001-0.25 parts of catalyst, and 0.1-10 parts of dispersant.

[0032] In a preferred embodiment of the present invention, the ratio of LA segment to GA segment of the PLGA initiator is (10:90-90:10), the purity of glycolide and lactide is ≥99.9%, the acid content of glycolide and lactide is ≤1000ppm, and the water content is ≤1000ppm.

[0033] In a preferred embodiment of the present invention, lactide is at least one of L-lactide, D-lactide, and D,L-lactide.

[0034] In a preferred embodiment of the present invention, the catalyst is selected from at least one of stannous octoate, stannous acetate, stannous chloride, and dibutyltin oxide; the dispersant is selected from at least one of toluene, cyclohexane, dichloromethane, and ethyl acetate.

[0035] In a preferred embodiment of the present invention, the melting and heat preservation temperature is 180-200℃, and the heat preservation time is 2-15min.

[0036] In a preferred embodiment of the present invention, the programmed cooling reaction includes a first temperature stage, a second temperature stage, and a third temperature stage proceeding sequentially. The holding times of the first and second stages are strictly controlled by the quasi-first-order open-loop kinetic equations of the system: The third stage is controlled by the peak torque. The first temperature stage involves polymerization at 180-200℃, with the reaction time sufficient for a glycolide monomer conversion exceeding 70%-90%. The second temperature stage involves polymerization at 160-180℃, with the reaction time sufficient for a lactide conversion exceeding 70%-90%. The third stage involves polymerization at 140-160℃, with the torque change rate during reaction time approaching 0-0.1.

[0037] In a preferred embodiment of the present invention, the kinetic equations are all based on the conversion rates of each monomer at a specific temperature.

[0038] In a preferred embodiment of the present invention, S1-S3 are all carried out in a twin-cone screw extruder, and the stirring speed of the twin-cone screw extruder is 10-200 rpm.

[0039] In a preferred embodiment of the present invention, the torque change rate can be determined from the twin cone screw extruder.

[0040] In a preferred embodiment of the present invention, the PLGA particles have a diameter of 1-10 mm and a length of 1-20 mm.

[0041] In a preferred embodiment of the invention, the number following PLGA represents the molar ratio of lactic acid (LA) to glycolic acid (GA). For example, PLGA8020 indicates that the ratio of LA segments to GA segments in the copolymer is 80:20.

[0042] In a preferred embodiment of the present invention, S1-S3 are all carried out under the protection of an inert gas, wherein the inert gas is nitrogen, argon or helium.

[0043] Unless otherwise specified, "parts" in the embodiments of this invention refer to the number of parts by weight.

[0044] All raw materials used in the embodiments of this invention were purchased commercially.

[0045] In a preferred embodiment of the present invention, the conversion rate is obtained by 1H NMR spectroscopy.

[0046] In the embodiments of this invention, molecular weight data and spectra were determined using advanced polymer permeation chromatography (APC).

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

[0048]

Example 1

[0049]

Example 2

[0050]

Example 3

[0051]

Example 4

[0052] Comparative Example 1 First, the temperature of all areas inside the twin cone screw extruder was set to 200°C using the heating program. At the same time, the interior was made into a nitrogen environment by displacement. The speed of the twin cone screw extruder was set to 50 rpm. 160 parts of L-lactide and 40 parts of glycolide were added and kept at this temperature for 5 minutes. 0.05 parts of stannous octoate and 0.01 parts of initiator were dispersed in 1 part of toluene, and then added to a twin-cone screw extruder. The mixture was kept for 5 minutes and reacted for 1.36 hours. PLGA with a weight-average molecular weight (Mw) of 22698 and an intrinsic viscosity of 0.3 dL / g was obtained.

[0053] Comparative Example 2 First, the temperature of all areas inside the twin cone screw extruder is set to 195°C through the heating program. At the same time, the internal environment is made into a nitrogen environment by displacement. The speed of the twin cone screw extruder is set to 50 rpm. 100 parts of PLGA8020 particles with a weight average molecular weight of 102563 are added to the twin cone screw extruder as an initiator and kept at the temperature for 5 minutes. Disperse 0.03 parts of stannous acetate in 1 part of cyclohexane, then add it to a twin cone screw extruder and circulate and mix it with molten PLGA8020 initiator for 8 minutes to obtain a mixture; Continue adding 10 parts glycolide and 60 parts L-lactide monomer to the twin-cone screw extruder and maintain for 5 minutes. React at this temperature for 1.5 hours. PLGA with a weight-average molecular weight (Mw) of 145698 and an intrinsic viscosity of 1.32 dL / g is obtained.

[0054] Comparative Example 3 First, the temperature of the twin-cone screw extruder was set to 150°C in all areas, and a nitrogen atmosphere was created by displacement. The extruder speed was set to 50 rpm. 30 parts glycolide and 70 parts D,L-lactide were added to the extruder and kept at this temperature for 8 minutes. Then, 0.05 parts stannous chloride and 0.02 parts lauryl alcohol were dispersed in 0.5 parts dichloromethane and kept at this temperature for 8 minutes. After reacting for 24 hours, PLGA with a weight-average molecular weight (Mw) of 12561 and an intrinsic viscosity of 0.12 dL / g was obtained.

[0055] Table 1. Summary of data from the examples and comparative examples

[0056] The synthesis processes of Comparative Examples 1 and 3 do not involve two-stage polymerization, therefore, there is no data for the comparative examples before the reaction.

[0057] As shown in Table 1, using a PLGA prepolymer of a certain molecular weight as a macromolecular initiator, and adding glycolide and lactide monomers to carry out ring-opening polymerization in a catalyst system, PLGA products with higher molecular weight and greater intrinsic viscosity can be prepared. Furthermore, by precisely planning the reaction time based on reaction kinetic data and supplementing it with a programmed cooling process, side reactions can be effectively suppressed, significantly improving the final monomer conversion rate of the system.

[0058] 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 novel method for preparing random high molecular weight PLGA, characterized in that... Includes the following steps: S1 uses PLGA particles with a weight-average molecular weight of 100,000-150,000 as an initiator, and melts and holds them at a constant temperature under an inert gas protection. S2 adds a catalyst and an initiator to the reaction system to obtain a blend; S3 adds a certain proportion of glycolide and lactide to the reactor and uses a programmed stage cooling method to conduct copolymerization experiments, producing PLGA with a weight average molecular weight of 150,000-250,000.

2. The method for preparing the polymer according to claim 1, characterized in that, By weight, the amounts of each raw material are as follows: 100 parts PLGA initiator, 1-150 parts glycolide monomer, 1-150 parts lactide monomer, 0.001-0.3 parts catalyst, and 0.1-10 parts dispersant.

3. The method for preparing the polymer according to claim 1, characterized in that, The ratio of LA segment to GA segment in the PLGA initiator is (10:90-90:10), the purity of glycolide and lactide is ≥99.9%, the acid content of glycolide and lactide is ≤1000ppm, and the water content is ≤1000ppm.

4. The preparation method according to claim 1, characterized in that, The catalyst is selected from one or more of stannous octoate, stannous chloride, stannous oxalate, stannous acetate, zinc lactate, zinc bromide, aluminum isopropoxide, and aluminum chloride; the dispersant is selected from one or more of toluene, dimethyl carbonate, cyclohexane, isopropanol, and ethyl acetate.

5. The method for preparing the polymer according to claim 1, characterized in that... The melting and heat preservation temperature is 160℃, and the heat preservation time is 2-15 minutes.

6. The method for preparing the polymer according to claim 1, characterized in that... The programmed cooling reaction comprises a first temperature stage, a second temperature stage, and a third temperature stage, proceeding sequentially. The holding times for the first and second stages are strictly controlled by the pseudo-first-order open-loop kinetic equations of this system: The third stage is controlled by the peak torque. The first temperature stage involves polymerization at 180-200℃, with the reaction time sufficient for a glycolide monomer conversion exceeding 70%-90%. The second temperature stage involves polymerization at 160-180℃, with the reaction time sufficient for a lactide conversion exceeding 70%-90%. The third stage involves polymerization at 140-160℃, with the reaction time sufficient for a torque change rate close to 0-0.

1.

7. The method for preparing the polymer according to claim 1, characterized in that, S1-S3 are all carried out in a twin cone screw extruder, and the stirring speed of the twin cone screw extruder is 10-200 rpm.

8. The method for preparing the polymer according to claim 1, characterized in that, PLGA particles have a diameter of 1-10mm and a length of 1-20mm.

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