Preparation method of high-purity poly-p-dioxanone

Abstract

The application provides a preparation method of high-purity poly-p-dioxanone, comprising the following steps: (1) mixing p-dioxanone monomer with a catalyst and an initiator, and performing a polymerization reaction under heating and negative pressure conditions; (2) adding an end-capping agent to the reaction system obtained in the step (1) and performing an end-capping reaction under heating and negative pressure conditions; the end-capping agent is one or more of n-alkyl isocyanate, aliphatic carboxylic acid, aliphatic carboxylic anhydride, benzoic acid, benzoic anhydride and alkyl-substituted oxirane; and (3) performing vacuum extraction on the reaction system obtained in the step (2) under heating conditions to obtain high-purity poly-p-dioxanone. The method can greatly reduce the residual amount of PDO under the premise of increasing the degradation period of PPDO.

Description

Technical Field

[0001] This invention relates to a method for preparing high-purity poly(p-dioxanone), belonging to the field of biomedical polymer materials. Background Technology

[0002] Poly(p-dioxanone) (PPDO) is an aliphatic polyether ester with excellent biocompatibility and biodegradability. It degrades in vivo to glyoxylic acid, which is excreted in urine, and can further degrade to glycine, posing no toxicity to humans. Due to the unique ether bonds in its molecular chain, it possesses both high strength and excellent flexibility. Through proper processing, it can be used to obtain biomaterials with both superior strength and toughness, making it highly suitable for use as biodegradable sutures and other biomaterials.

[0003] The ring-opening polymerization of p-dioxanone (PDO) is a reversible thermodynamic equilibrium reaction. Under conventional preparation conditions, the monomer conversion rate in PPDO is low, resulting in a high monomer residue in the finished product. Taking the preparation reaction conditions using stannous octoate as a catalyst as an example, the PDO conversion rate under different conditions is only 67% (US patent 5652331, WO9721753) and 79.4% (Macromolecules 2000, 33, 6982-6986). Therefore, the purification of PPDO is a significant challenge in its application.

[0004] To reduce monomer residue in finished PPDO, the main solution is to remove monomers through post-processing of the crude product under high temperature and high vacuum conditions. However, as the monomers volatilize, the polymer gradually agglomerates, encapsulating the residual monomers and hindering their volatilization; while excessively high extraction temperatures can lead to polymer depolymerization. Patent document CN113698586A discloses a method for preparing and using medical ultra-high molecular weight poly(p-dioxanone), which involves cooling and pulverizing PPDO containing a large amount of monomers with liquid nitrogen, followed by vacuum extraction at 40-100°C to remove the monomers. The core of this process lies in the fact that the liquid nitrogen cooling process freezes the bicontinuous morphology of the monomers and polymers. During vacuum extraction, the monomers can volatilize through channels they form themselves. At this point, the PPDO has formed structurally stable crystals and cannot further agglomerate. Although this method can effectively purify PPDO, its liquid nitrogen cooling process is energy-intensive and difficult to scale up. Patent CN110028658A discloses an ultrasonic synthesis method for poly(p-dioxanone) polymers to avoid the use of catalysts, and after the reaction, an alcohol-based end-capping agent is added, followed by vacuum extraction of impurities at 160℃-170℃. The core of this process lies in using an alcohol-based end-capping agent to seal the carboxyl ends of PPDO, followed by vacuum extraction of impurities at a higher temperature. While this method solves the problem of impurities being difficult to volatilize during vacuum evaporation to some extent, the pyrolysis of PPDO is caused by the attack of active hydroxyl groups on PPDO (Polym. Degrd. Stab., 2000, 70, 485-96). This method does not seal the active hydroxyl groups on PPDO, and even introduces new end-capping agents containing hydroxyl groups. Therefore, it does not solve the problem of PPDO molecular chain breakage and molecular weight reduction during the process. Furthermore, this patent does not report the molecular weight of the product or the monomer residual rate. Summary of the Invention

[0005] To address the issue of high PDO monomer residue in PPDO materials prepared by conventional methods, this invention provides a simple and efficient method for preparing high-purity poly(p-dioxanone), which can significantly reduce PDO residue while increasing the PPDO degradation cycle.

[0006] This invention is achieved through the following technical solution:

[0007] A method for preparing high-purity poly(p-dioxanone) comprises the following steps:

[0008] (1) The dioxane monomer is mixed with a catalyst and an initiator and polymerized under heating and negative pressure conditions;

[0009] (2) Add a capping agent to the reaction system obtained in step (1) and carry out the capping reaction under heating and negative pressure conditions; the capping agent is one or more of the following: n-alkyl isocyanate, aliphatic carboxylic acid, aliphatic carboxylic anhydride, benzoic acid, benzoic anhydride and alkyl-substituted ethylene oxide;

[0010] (3) Under heating conditions, the reaction system obtained in step (2) is vacuum extracted to obtain high-purity poly(p-dioxane).

[0011] Preferably, in step (1), the dioxane monomer is pre-purified by distillation.

[0012] Preferably, in step (1), the catalyst is one or more of stannous octoate, dibutyltin dilaurate, stannous oxalate, dibutyltin oxide, and tetrabutyltin; the amount of catalyst added is 0.1‰-2‰ of the mass of the dioxane monomer.

[0013] Preferably, in step (1), the initiator is a diol with 2-8 carbon atoms.

[0014] Preferably, in step (1), the amount of initiator added is 0.1‰-5‰ of the mass of dioxane-1,4-dioxanone monomer.

[0015] Preferably, in step (1), the heating temperature is 80-140℃, the negative pressure is 2-50Pa, and the reaction time is 4-72 hours.

[0016] Preferably, in step (2), the amount of the capping agent added is 2-100 times the amount of the initiator.

[0017] Preferably, in step (2), the heating temperature is 80-140℃, the negative pressure is 2-50Pa, and the reaction time is 1-4 hours.

[0018] Preferably, in step (3), the heating temperature is 140-180℃, the pressure is less than or equal to 20Pa, and the vacuum extraction time is 1-10 hours.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] This invention, based on conventional end-capping or vacuum purification and combined with a series of studies on PPDO degradation, uses end-capping agents such as carboxylic acids, acid anhydrides, isocyanates, and epoxy resins. The key lies in sealing the active hydroxyl groups at the molecular chain ends. Since the pyrolysis of PPDO is a "zipper-unzipping" process, the active hydroxyl groups at the molecular chain ends or those generated by PDO ring opening attack the ether-ester bonds within the molecular chain, causing chain breakage or the shedding of individual rings. The activation energy of the active hydroxyl group attacking the ether-ester bond is much lower than the activation energy of temperature-induced breakage of the ether-ester bond within PPDO. Therefore, using a hydroxyl-free end-capping agent to seal the active hydroxyl groups at the molecular chain ends can effectively reduce the attack of active hydroxyl groups on the ether-ester bond, thereby significantly reducing the degradation rate of PPDO. Therefore, the end-capping method disclosed in this invention not only solves the problems of PPDO molecular chain breakage and molecular weight reduction during purification but also further extends the degradation cycle of purified PPDO. Attached Figure Description

[0021] Figure 1 The NMR spectra of Example 1 before (top) and after (bottom) the removal of monomers;

[0022] Figure 2 Thermolytic resistance of high-purity poly(p-dioxane) prepared in Comparative Example 1 and Example 3 was compared (TGA).

[0023] Figure 3 The NMR spectra of Comparative Example 1 (top) and Example 3 (bottom) after removing the monomers are shown.

[0024] Figure 4 The change in molecular weight (GPC) before and after purification in Example 4. Detailed Implementation

[0025] To further understand the present invention, the present invention will be described below with reference to embodiments. These descriptions are only for further explaining the features and advantages of the present invention and are not intended to limit the claims of the present invention.

[0026] The method for preparing high-purity poly(p-dioxanone) according to the present invention includes the following steps:

[0027] (1) The dioxane monomer, catalyst, and initiator are thoroughly mixed in a reactor and polymerized under heating and negative pressure conditions.

[0028] (2) Add a capping agent to the reaction vessel and carry out a capping reaction; the capping agent is one or more of the following: n-alkyl isocyanate (alkyl carbon atoms number 2-8), aliphatic carboxylic acid and its anhydride (carboxylic acid carbon atoms number 2-8), benzoic acid and its anhydride and alkyl-substituted ethylene oxide (alkyl carbon atoms number 2-6).

[0029] (3) Increase the temperature and vacuum of the reactor to vacuum extract small molecule impurities such as monomers and catalysts.

[0030] (4) Lower the temperature of the reactor to room temperature and discharge the material to obtain high-purity polydioxanone.

[0031] In step (1), the p-dioxanone monomer is purified by distillation before the reaction.

[0032] In step (1), the catalyst is one or more of stannous octoate, dibutyltin dilaurate, stannous oxalate, dibutyltin oxide, and tetrabutyltin, and the amount added is 0.1‰-2‰ of the mass of the dioxane monomer.

[0033] In step (1), the initiator comprises a diol having 2-8 carbon atoms, and the amount added is 0.1‰-5‰ of the mass of the dioxane monomer.

[0034] In step (1), the reaction temperature is 80-140℃, the pressure inside the reactor is 2-50Pa, and the reaction time is 4-72 hours.

[0035] In step (2), the amount of capping agent added is 2-100 times (in amount of substance) of the initiator.

[0036] In step (2), the reaction temperature is 80-140℃, the pressure inside the reactor is 2-50Pa, and the reaction time is 1-4 hours.

[0037] In step (3), the heating temperature is 140-180℃, the pressure is less than or equal to 20Pa, and the vacuum extraction time is 1-10 hours.

[0038] Example 1

[0039] (1) The dioxane monomer was mixed with stannous octoate catalyst and propanol initiator. The amount of stannous octoate added was 0.3‰ of the monomer mass, and the amount of propanol added was 0.1‰ of the monomer mass. The ring-opening polymerization reaction was carried out for 72 hours under the conditions of vacuum degree of 20 Pa and temperature of 110 °C.

[0040] (2) Add 20 times the amount of initiator to the reaction system after the ring-opening polymerization, heat to 120°C, maintain a vacuum of 20 Pa, and carry out the end-capping reaction for 3 hours.

[0041] (3) After the end-capping reaction is completed, heat the reactor to 180°C, maintain the pressure <10Pa, and continue extraction for 6 hours.

[0042] (4) Quickly reduce the temperature of the reactor to room temperature and discharge the material to obtain high-purity polydioxanone.

[0043] As determined by nuclear magnetic resonance hydrogen spectroscopy, Figure 1 In this embodiment, the residual PDO content in polydioxanone decreased from 24.5% before extraction to 0.7%.

[0044] Example 2

[0045] (1) The dioxane monomer was mixed with stannous octoate catalyst and propanol initiator. The amount of stannous octoate added was 5‰ of the monomer mass and the amount of propanol added was 1‰ of the monomer mass. The ring-opening polymerization reaction was carried out for 36 hours under the conditions of vacuum degree of 40 Pa and temperature of 100 °C.

[0046] (2) Add 15 times the amount of initiator to the reaction system after the ring-opening polymerization, heat to 110°C, maintain a vacuum of 40 Pa, and carry out the end-capping reaction for 2 hours.

[0047] (3) After the end-capping reaction is completed, heat the reactor to 150°C, maintain the pressure <10Pa, and continue extraction for 1 hour.

[0048] (4) Quickly reduce the temperature of the reactor to room temperature and discharge the material to obtain high-purity polydioxanone.

[0049] According to the proton nuclear magnetic resonance spectroscopy, the residual PDO in the polydioxanone obtained in this example decreased from 23.1% before extraction to 1.8%.

[0050] Example 3

[0051] (1) The dioxane monomer was mixed with stannous octoate catalyst and propanol initiator. The amount of stannous octoate added was 2‰ of the monomer mass, and the amount of propanol added was 2‰ of the monomer mass. The ring-opening polymerization reaction was carried out for 16 hours under the conditions of vacuum degree of 5 Pa and temperature of 120℃.

[0052] (2) Add acetic acid, twice the amount of the initiator, to the reaction system after the ring-opening polymerization is completed, heat to 130°C, maintain a vacuum of 5 Pa, and carry out the end-capping reaction for 2 hours.

[0053] (3) After the end-capping reaction is completed, heat the reactor to 170°C, maintain the pressure <15Pa, and continue extraction for 4 hours.

[0054] (4) Quickly reduce the temperature of the reactor to room temperature and discharge the material to obtain high-purity polydioxanone.

[0055] According to the proton nuclear magnetic resonance spectroscopy, the residual PDO in the polydioxanone obtained in this example decreased from 29.3% before extraction to 2.6%.

[0056] Example 4

[0057] (1) The dioxane monomer was mixed with stannous octoate catalyst and propanol initiator. The amount of stannous octoate added was 0.1‰ of the monomer mass, and the amount of propanol added was 1.5‰ of the monomer mass. The ring-opening polymerization reaction was carried out for 24 hours under the conditions of vacuum degree of 10 Pa and temperature of 110 °C.

[0058] (2) Add 100 times the amount of initiator to the reaction system after the ring-opening polymerization, heat to 130°C, maintain a vacuum of 5 Pa, and carry out the end-capping reaction for 2 hours.

[0059] (3) After the end-capping reaction is completed, the reactor is heated to 140°C, the pressure is kept <15Pa, and extraction is continued for 4 hours.

[0060] (4) Quickly reduce the temperature of the reactor to room temperature and discharge the material to obtain high-purity polydioxanone.

[0061] According to the proton nuclear magnetic resonance spectroscopy, the residual PDO in the poly(p-dioxanone) obtained in this example decreased from 28.3% before extraction to 2.0%.

[0062] Comparative Example 1

[0063] (1) The dioxane monomer was mixed with stannous octoate catalyst and propanol initiator. The amount of stannous octoate added was 2‰ of the monomer mass, and the amount of propanol added was 2‰ of the monomer mass. The ring-opening polymerization reaction was carried out for 16 hours under the conditions of vacuum degree of 5 Pa and temperature of 120℃.

[0064] (2) After the polymerization reaction is completed, the reactor is heated to 170°C, the pressure is kept <15Pa, and extraction is continued for 4 hours.

[0065] (3) Quickly reduce the temperature of the reactor to room temperature and discharge the material to obtain polydioxanone.

[0066] Compared with Example 3, Comparative Example 1 did not add a capping agent for the capping reaction, but all other conditions were exactly the same as in Example 3. Figure 2 This is a comparison of the pyrolysis resistance of poly(p-dioxanone) prepared in Comparative Example 1 and Example 3. Figure 2 The dashed line represents PPDO capped with carboxylic acid (Ac) (PPDO-Ac), which exhibits significantly improved pyrolysis resistance compared to the uncapped PPDO in Comparative Example 1. Specific analysis revealed key degradation points (as shown in Table 1). At a heating rate of 10 °C / min, the remaining mass of Ac-capped PPDO at 160 °C was 3.7% greater than that of the uncapped PPDO, representing an approximately 46.8% improvement in pyrolysis resistance. Furthermore, at subsequent stages of remaining mass, the degradation temperature of Ac-capped PPDO also showed a significant increase.

[0067] Table 1 shows the pyrolysis information (TGA) of PPDO before and after acetic acid capping.

[0068] PPDO 202 253 268 92.1 PPDO-Ac 230 254 263 95.8

[0069] Figure 3 The NMR spectra of Comparative Example 1 and Example 3 after monomer removal show that the end-capping process in Example 3 can remove monomer more cleanly, while the uncapped sample in Comparative Example 1 will have more monomer residue due to pyrolysis.

[0070] like Figure 4 Table 2 shows the molecular weight and molecular weight distribution data of poly(p-dioxanone) before and after purification in Example 4.

[0071] Table 2 shows the molecular weight change (GPC) before and after purification in Example 4.

[0072]

[0073] from Figure 4 As shown in Table 2, the molecular weight of PPDO decreased from 314,400 to 268,500 after purification, while the molecular weight distribution decreased from 4.66 to 4.29. Although the molecular weight still decreased, the degree of decrease was still within an acceptable range, and no large-scale pyrolysis occurred.

Claims

1. A method for preparing high-purity poly(p-dioxanone), characterized in that, Includes the following steps: (1) Mix p-dioxanone monomer with catalyst and initiator and carry out polymerization reaction under heating and negative pressure conditions; heating temperature is 80-140℃, negative pressure is 2-50Pa, and reaction time is 4-72 hours. (2) Add a capping agent to the reaction system obtained in step (1) and carry out the capping reaction under heating and negative pressure conditions; the capping agent is one of acetic anhydride, acetic acid, ethyl ethylene oxide and n-butyl isocyanate; the heating temperature is 80-140℃, the negative pressure is 2-50Pa, and the reaction time is 1-4 hours. (3) Under heating conditions, the reaction system obtained in step (2) is vacuum extracted to obtain high-purity poly(p-dioxane).

2. The method for preparing high-purity poly(p-dioxane) ketone according to claim 1, characterized in that, In step (1), the dioxane monomer is purified in advance by distillation.

3. The method for preparing high-purity poly(p-dioxane) ketone according to claim 1, characterized in that, In step (1), the catalyst is one or more of stannous octoate, dibutyltin dilaurate, stannous oxalate, dibutyltin oxide, and tetrabutyltin; the amount of catalyst added is 0.1‰-2‰ of the mass of dioxane monomer.

4. The method for preparing high-purity poly(p-dioxane) ketone according to claim 1, characterized in that, In step (1), the initiator is a diol with 2-8 carbon atoms.

5. The method for preparing high-purity poly(p-dioxane) ketone according to claim 1, characterized in that, In step (1), the amount of initiator added is 0.1‰-5‰ of the mass of dioxane monomer.

6. The method for preparing high-purity poly(p-dioxane) ketone according to claim 1, characterized in that, In step (2), the amount of capping agent added is 2-100 times the amount of initiator.

7. The method for preparing high-purity poly(p-dioxane) ketone according to claim 1, characterized in that, In step (3), the heating temperature is 140-180℃, the pressure is less than or equal to 20Pa, and the vacuum extraction time is 1-10 hours.

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