Method for controllable polymerization of poly (p-dioxanone) by using combination of high-purity p-dioxanone monomer and stabilizer

Abstract

The invention discloses a method for controllable polymerization of poly (p-dioxanone) by using a combination of a high-purity p-dioxanone monomer and a stabilizer, belongs to the technical field of medical degradable high polymer materials, and particularly relates to a method for controllable polymerization of poly (p-dioxanone) by using a combination of a high-purity p-dioxanone monomer and a stabilizer. The method comprises the following specific implementation steps: step 1, preparing a high-purity PDO monomer; 2, preparing a compound stabilizer composition; 3, mixing a monomer and a stabilizer; and 4, carrying out a controllable polymerization reaction to realize the controllability of the polymerization process, and finally obtaining the PPDO product with high molecular weight, narrow molecular weight distribution and low residual monomer content. According to the method, the defects of chain transfer, side reaction increase and unstable molecular weight in the ring-opening polymerization process can be avoided, meanwhile, the side reaction can be well inhibited, the polymerization efficiency and the performance of a final product can be guaranteed, and the final product PPDO is high in safety and meets the requirements of medical materials.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical degradable polymer materials, more particularly to a method for controllable polymerization of poly-p-dioxanone by using high-purity p-dioxanone monomer and stabilizer combination. BACKGROUND

[0002] PPDO (poly-p-dioxanone) is widely used in the medical field, especially in medical sutures, stents and drug controlled-release carriers. In the field of medical sutures, PPDO is widely used in various surgeries due to its excellent biocompatibility and absorbability, especially in fine operations such as soft tissue suturing, pediatric cardiovascular tissue suturing and ophthalmic surgery. In the field of stents, PPDO is often used to make vascular stents, esophageal stents and other implanted devices to provide a good environment for cell adhesion and proliferation, thereby promoting tissue regeneration and repair. In addition, PPDO can effectively load and slowly release drugs in the field of drug controlled-release carriers, prolong the action time of drugs and improve the therapeutic effect.

[0003] At present, the PDO monomer in the existing process contains water, residual acid or trace metal impurities, which will cause chain transfer, increase of side reactions and instability of molecular weight in the ring-opening polymerization process. Single antioxidant or acid capture agent cannot completely inhibit the side reactions, affecting the polymerization efficiency and the performance of the final product.

[0004] Therefore, in view of the above, the existing structure is improved, and a method for controllable polymerization of poly-p-dioxanone by using high-purity p-dioxanone monomer and stabilizer combination is provided, so as to achieve a more practical purpose. SUMMARY

[0005] 1. Technical problem to be solved In view of the problems in the prior art, the purpose of the present application is to provide a method for controllable polymerization of poly-p-dioxanone by using high-purity p-dioxanone monomer and stabilizer combination, which can avoid the disadvantages of chain transfer, increase of side reactions and instability of molecular weight in the ring-opening polymerization process, and can better inhibit the side reactions, ensure the polymerization efficiency and the performance of the final product, and the safety of the final product PPDO is high, which meets the requirements of medical materials.

[0006] 2. Technical scheme In order to solve the above problems, the technical scheme adopted by the present application is as follows.

[0007] A method for controllable polymerization of poly-p-dioxanone by using high-purity p-dioxanone monomer and stabilizer combination, the specific implementation steps of the method are as follows: Step 1, preparation of high-purity PDO monomer: dry and purify the p-dioxanone monomer to meet the purity standard; Step two, preparation of composite stabilizer combination: prepare antioxidant, acid capture agent, complexing agent, weigh and mix to form composite stabilizer; Step three, mixing monomer and stabilizer: before the start of the polymerization reaction, the composite stabilizer prepared in step two is added to the high purity PDO monomer prepared in step one, and then the stabilizer is uniformly dispersed in the PDO monomer by stirring; Step four, controlled polymerization reaction to obtain the final PPDO product: place the uniformly mixed monomer and stabilizer system in a polymerization reaction device under the set polymerization conditions, continuously stir, then perform ring-opening polymerization reaction to achieve controllability of the polymerization process, and finally obtain a PPDO product with high molecular weight, narrow molecular weight distribution, and low residual monomer content.

[0008] Further, in step one, the purity standard of the prepared high-purity PDO monomer is: Monomer purity ≥ 99.5%; Moisture content ≤ 500 ppm; Residual acid content ≤ 50 ppm.

[0009] Further, in step one, the drying and purification treatment of dioxanone monomer includes recrystallization and molecular distillation; The solvent used for recrystallization is anhydrous ethanol or super-dry ethyl acetate, and the number of recrystallization is not less than 2 times; Molecular distillation is carried out at a temperature of 80-100°C and a pressure of less than 10 Pa.

[0010] Further, in step two, when the composite stabilizer combination is configured: The antioxidant is selected from BHT or Irganox 1010, which is used to inhibit side reactions initiated by free radicals; The acid capture agent is selected from calcium carbonate or magnesium oxide, which is used to neutralize residual acid and inhibit chain termination reactions; The complexing agent is selected from EDTA or phosphonate, which is used to chelate trace metal ions to prevent side reactions caused by catalysts or impurities.

[0011] Further, in step two, the weighing amount of antioxidant, acid capture agent, and complexing agent relative to the PDO monomer is: Antioxidant: 0.05wt%; Acid capture agent: 0.05wt%; Complexing agent: 0.05wt%.

[0012] Further, in step three, the mixing process is carried out under inert gas protection, the stirring speed is 200-500 rpm, and the stirring time is 30-60 minutes to ensure that the composite stabilizer forms a uniform suspension or dissolution system in the PDO monomer.

[0013] Further, in the step four, the set polymerization conditions are: Temperature: 150°C Pressure: vacuum environment; Time: 2 hours.

[0014] Further, in the step four, the polymerization device is equipped with a high-precision temperature control system and an online viscosity monitor. The catalyst used in the ring-opening polymerization reaction is stannous octoate, and the addition amount is 0.01-0.05wt% of the total mass of the monomer, and the catalyst is added after the monomer is uniformly mixed with the stabilizer.

[0015] Further, in the step four, the number average molecular weight (Mn) of the finally obtained PPDO product is ≥ 1.0×10^5g / mol, the molecular weight distribution index (PDI) is ≤ 1.8, and the residual monomer content in the polymer is less than 1.0wt%.

[0016] 3. Beneficial effects Compared with the prior art, the advantages of the present application are: In this scheme, the stabilizer is uniformly added to the PDO monomer before polymerization; during the polymerization process, the combination of high-purity monomer and stabilizer inhibits side reactions, improves polymerization efficiency and molecular weight stability, wherein the high-purity monomer reduces the influence of moisture / residual acid on chain transfer, and the synergistic effect of the composite stabilizer effectively inhibits side reactions, improves the number average molecular weight and molecular weight distribution stability of PPDO, avoids the disadvantages of chain transfer, increased side reactions, and unstable molecular weight during ring-opening polymerization, and at the same time, can better inhibit side reactions, ensure polymerization efficiency and product performance, and the safety of the final product PPDO is high, meeting the requirements of medical materials. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 The flowchart shows the method of using high-purity p-dioxanone monomer and stabilizer combination for controlled polymerization of p-dioxanone in the present application. DETAILED DESCRIPTION

[0018] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application; obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0019] Example 1: Please refer to Figure 1A method for controllable polymerization of poly-p-dioxanone by using high-purity p-dioxanone monomer and stabilizer combination, the specific implementation steps of the method are as follows: Step one, preparation of high-purity PDO monomer: dry and purify the p-dioxanone monomer to meet the purity standard; Specifically, the purity standard of the prepared high-purity PDO monomer is: Monomer purity ≥ 99.5%; Moisture content ≤ 500 ppm; Residual acid content ≤ 50 ppm.

[0020] Quantitatively ensure the "cleanliness" of the reaction system: High purity (≥ 99.5%) ensures the consistency of the reaction main body, reduces the occurrence of side reactions; low moisture (≤ 500 ppm) effectively prevents catalyst deactivation and chain growth termination caused by moisture; low residual acid (≤ 50 ppm) significantly inhibits acid-catalyzed chain scission and depolymerization side reactions. These three indicators together lay a solid foundation for high conversion rate and obtaining high molecular weight polymer.

[0021] Specifically, the drying and purification treatment of p-dioxanone monomer includes recrystallization and molecular distillation; The solvent used for recrystallization is anhydrous ethanol or super-dry ethyl acetate, and the recrystallization frequency is not less than 2 times; Molecular distillation is carried out at a temperature of 80-100°C and a pressure of less than 10 Pa.

[0022] The combination of recrystallization and molecular distillation purification technology realizes multi-stage deep removal of impurities. Recrystallization can effectively remove most of the soluble organic impurities; subsequent molecular distillation is carried out at low temperature and high vacuum, which can efficiently remove residual trace moisture, solvent and volatile impurities, while avoiding decomposition or polymerization of monomers due to high temperature. This process is clear, efficient, and easy to scale up, providing a reliable guarantee for stably obtaining ultra-high purity PDO monomer.

[0023] Step two, preparation of composite stabilizer combination: prepare antioxidants, acid scavengers, and binding agents, weigh and mix to form a composite stabilizer; Specifically, when configuring the composite stabilizer combination: The antioxidant is BHT or Irganox 1010, which is used to inhibit side reactions initiated by free radicals; The acid scavenger is calcium carbonate or magnesium oxide, which is used to neutralize residual acid and inhibit chain termination reaction; The complexing agent is EDTA or phosphonate, which is used to chelate trace metal ions to prevent side reactions caused by catalysts or impurities.

[0024] By the synergistic effect of the three of antioxidant, acid capture agent, complexing agent, a comprehensive stable protection system is constructed. The system can be targeted to inhibit free radical degradation, acid catalytic chain termination and metal ion catalytic side reaction, etc. three most important paths leading to polymerization out of control or polymer degradation. This "multi-target" stability strategy significantly improves the controllability and repeatability of the polymerization process, and improves the thermal stability and long-term stability of the product.

[0025] Specifically, the weighing parts of antioxidant, acid capture agent, and complexing agent relative to monomer PDO monomer are: Antioxidant: 0.05wt%; Acid capture agent: 0.05wt%; Complexing agent: 0.05wt%.

[0026] The addition ratio of 0.05wt% is the optimized balance point. This amount is sufficient to effectively exert its own function, achieve sufficient capture and inhibition of trace impurities; at the same time, this low addition amount avoids the risk of excessive stabilizer which may introduce new impurities, affect the catalyst activity, and even remain in the final polymer to damage its biocompatibility or mechanical properties. The ratio achieves the best balance between effect and side effect.

[0027] Step three, mixing monomer and stabilizer: before the start of the polymerization reaction, the composite stabilizer prepared in step two is added to the high purity PDO monomer prepared in step one, and then the stabilizer is uniformly dispersed in the PDO monomer by stirring; Specifically, the mixing process is carried out under the protection of inert atmosphere, the stirring speed is 200-500 rpm, and the stirring time is 30-60 minutes, to ensure that the composite stabilizer forms a uniform suspension or dissolution system in the PDO monomer.

[0028] First, operating under an inert atmosphere (such as nitrogen or argon) can completely eliminate the interference of oxygen and moisture, providing an absolutely clean environment for the mixing process. Second, by controlling the stirring speed and time (200-500 rpm, 30-60 min), the stabilizer, especially the micron or nanometer scale solid acid capture agent (such as calcium carbonate), can be uniformly dispersed at the molecular level in the monomer, forming a uniform reaction starting system, which is conducive to the synchronization of subsequent polymerization reaction and obtaining a narrow molecular weight distribution.

[0029] Step four, perform a controllable polymerization reaction to obtain the final PPDO product: place the uniformly mixed monomer and stabilizer system in a polymerization reaction device under the set polymerization conditions, and continuously stir, then perform ring-opening polymerization reaction to realize the controllability of the polymerization process, and finally obtain a PPDO product with high molecular weight, narrow molecular weight distribution, and low residual monomer content.

[0030] Specifically, the set polymerization conditions are as follows: Temperature: 150°C Pressure: vacuum environment Time: 2 hours.

[0031] The temperature of 150°C is the best choice considering the reaction rate and controllability, and a temperature that is too high can easily lead to thermal degradation, and a temperature that is too low can cause the reaction to be too slow; the vacuum environment can timely remove small molecular byproducts generated during the reaction (if any), and continuously maintain an oxygen-free and water-free reaction atmosphere, thereby promoting the reaction equilibrium to move in the direction of generating polymers; the reaction time of 2 hours is sufficient to ensure that the monomer conversion rate reaches a high level, while avoiding polymer degradation caused by long-term high-temperature heating.

[0032] Specifically, the polymerization device is equipped with a high-precision temperature control system and an online viscosity monitor. The catalyst used in the ring-opening polymerization reaction is stannous octoate, and the addition amount is 0.01-0.05 wt% of the total mass of the monomer, and the catalyst is added after the monomer is uniformly mixed with the stabilizer.

[0033] The high-precision temperature control system ensures that the reaction temperature fluctuates very little, ensuring batch-to-batch reproducibility; the online viscosity monitor can reflect the polymerization progress and molecular weight growth in real time, providing an intuitive basis for process control and end point determination, and achieving "visual" monitoring of the polymerization process. Stannous octoate is selected as the catalyst and its addition amount is controlled to be low (0.01-0.05 wt%), because it has high activity and selectivity for the ring-opening polymerization of lactide, p-dioxanone and other monomers, which is beneficial to obtain high molecular weight polymers, and it is relatively easy to remove in subsequent processing.

[0034] Specifically, the final obtained PPDO product has a number average molecular weight (Mn) of ≥ 1.0×10^5 g / mol, a molecular weight distribution index (PDI) of ≤ 1.8, and a residual monomer content in the polymer of less than 1.0 wt%.

[0035] The number average molecular weight (Mn) of ≥ 100,000 g / mol indicates that the polymerization reaction is sufficient and the chain growth is effective, meeting the basic requirements of molecular weight for high-performance materials; the molecular weight distribution index (PDI) of ≤ 1.8 is direct evidence of the high controllability of the polymerization process, indicating that the chain initiation and chain growth are relatively synchronized, and such polymers have more uniform mechanical properties and processing properties; The residual monomer content of less than 1.0 wt% indicates high conversion of the monomer, which not only improves the yield, but more importantly, reduces the plasticizing and degrading effect of small molecular monomers on the mechanical strength and thermal stability of the polymer, and improves the biological safety and application reliability of the product.

[0036] Example 2: Based on the above embodiment 1, further described.

[0037] According to the method in embodiment 1, PPDO products are prepared, and meanwhile, comparative method 1 (without stabilizer) and comparative method 2 (with single antioxidant) are established, and the operation conditions and results of the three groups of preparation processes are as follows: As shown in the chart, the high-purity p-dioxanone monomer and the stabilizer combination used in the method for controllable polymerization of poly-p-dioxanone can obtain good product performance of the PPDO product, and can better meet the use requirements.

[0038] The above description is only a preferred specific embodiment of the present application; however, the protection scope of the present application is not limited thereto. Any person skilled in the art can make equivalent replacements or changes according to the technical solution and the improvement concept of the present application within the technical range disclosed by the present application, which should be covered in the protection scope of the present application.

Claims

1. A method for the controlled polymerization of poly-p-dioxanone using a combination of high purity p-dioxanone monomer and a stabilizer, characterized by: The specific implementation steps of the method are as follows: Step 1: Preparation of high-purity PDO monomer: dry and purify the p-dioxanone monomer to meet the purity standard; Step 2: Preparation of composite stabilizer combination: prepare antioxidants, acid scavengers, and complexing agents, weigh and mix to form a composite stabilizer; Step 3: Mixing of monomer and stabilizer: before the start of the polymerization reaction, add the composite stabilizer prepared in step 2 to the high-purity PDO monomer prepared in step 1, then stir to ensure uniform dispersion of the stabilizer in the PDO monomer; Step 4: Perform controlled polymerization reaction to obtain the final PPDO product: place the uniformly mixed monomer and stabilizer system in a polymerization reaction device under the set polymerization conditions, continuously stir, then perform ring-opening polymerization reaction to achieve controllability of the polymerization process, and finally obtain a PPDO product with high molecular weight, narrow molecular weight distribution, and low residual monomer content.

2. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 1, the purity standard of the prepared high-purity PDO monomer is: Monomer purity ≥ 99.5%; Moisture content ≤ 500 ppm; Residual acid content ≤ 50 ppm.

3. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 1, the drying and purification treatment of the p-dioxanone monomer includes recrystallization and molecular distillation; The solvent used for recrystallization is anhydrous ethanol or super-dry ethyl acetate, and the recrystallization frequency is not less than 2 times; Molecular distillation is carried out at a temperature of 80-100°C and a pressure of less than 10 Pa.

4. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 2, when configuring the composite stabilizer combination: Antioxidants such as BHT or Irganox 1010 are used to inhibit side reactions initiated by free radicals; Acid scavengers such as calcium carbonate or magnesium oxide are used to neutralize residual acid and inhibit chain termination reactions; Complexing agents such as EDTA or phosphonate are used to chelate trace metal ions to prevent side reactions caused by catalysts or impurities.

5. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 2, the weighing amount of antioxidants, acid scavengers, and complexing agents relative to the PDO monomer is: Antioxidant: 0.05 wt%; Acid scavenger: 0.05 wt%; Complexing agent: 0.05 wt%.

6. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 3, the mixing process is carried out under inert gas protection, the stirring speed is 200-500 rpm, and the stirring time is 30-60 minutes to ensure that the composite stabilizer forms a uniform suspension or dissolution system in the PDO monomer.

7. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 4, the set polymerization conditions are: Temperature: 150°C Pressure: vacuum environment; Time: 2 hours.

8. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 4, the polymerization reaction device is equipped with a high-precision temperature control system and an online viscosity monitor; The catalyst used for ring-opening polymerization reaction is stannous octoate, and its addition amount is 0.01-0.05 wt% of the total mass of the monomer, and the catalyst is added after the monomer and stabilizer are uniformly mixed.

9. The method of claim 1, wherein the high purity p-dioxanone monomer and the stabilizer combination are used for controlled polymerization of poly-p-dioxanone. In step 4, the final PPDO product has a number average molecular weight (Mn) of ≥ 1.0×10^5 g / mol, a molecular weight distribution index (PDI) of ≤ 1.8, and a residual monomer content in the polymer of less than 1.0 wt%.

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