Method for preparing poly (p-dioxanone) through solution polymerization

Abstract

The invention discloses a method for preparing poly (p-dioxanone) through solution polymerization, which is characterized in that the poly (p-dioxanone) separated out in a powder form is obtained by performing ring-opening polymerization reaction on the poly (p-dioxanone) as a polymerization monomer in the presence of a catalyst and an aromatic hydrocarbon solvent under the anhydrous and anaerobic conditions under the protection of inert gas.

Description

Technical Field

[0001] The present invention relates to the field of polymer material preparation, and in particular to a method for preparing poly(p-dioxanone) by ring-opening polymerization of p-dioxanone using a solution polymerization method. Background Art

[0002] Poly(p-dioxanone) (PPDO) is an aliphatic polyester-ether. The ester bond in its main molecular chain gives the polymer excellent biodegradability, biocompatibility and bioabsorbability. In addition, due to the unique ether bond in its main molecular chain, the polymer has excellent physical and mechanical properties such as flexibility while having good strength. Therefore, PPDO is an ideal medical biodegradable material. In the 1970s, PPDO was successfully used by Ethicon, a subsidiary of Johnson & Johnson in the United States, to prepare degradable surgical sutures, with the trade name PDS. At present, in addition to being used in the manufacture of absorbable surgical sutures, PPDO is also used in orthopedic fixation materials and tissue repair materials such as orthopedic fixation devices such as screws, fixation bolts, pins, anchors, hoops and bone plates, hemostatic forceps, hemostatic ointments, suture clips, medicinal screens and medical adhesives. On the other hand, compared with some aliphatic polyesters that have been commercialized in the field of environmental materials, PPDO has excellent comprehensive performance and outstanding monomer recovery. Under reduced pressure in the temperature range of 150-250°C, an unzipping depolymerization reaction can occur, and the monomer para-dioxanone (PDO) is finally obtained. Moreover, under suitable conditions, the monomer recovery rate is as high as 99.3%, and the recovered monomer can be used to synthesize PPDO. Therefore, PPDO is very suitable for the production of disposable plastic products. When it is discarded after completing its use function, the collected waste can be used to recover the monomer, and then the recovered monomer is polymerized into new PPDO material for repeated use. For application areas that are not suitable for recycling, PPDO can be biodegraded and does not pollute the environment. It can be seen that PPDO is a truly low-carbon and environmentally friendly product.

[0003] However, the industrialization of polydioxanone has certain difficulties. Specifically, in order to achieve large-scale production, the polymer after the polymerization of polydioxanone must be easily discharged from the reactor, and the unreacted monomer must be effectively removed. However, polydioxanone is thermally unstable, and when it is heated to a high temperature in order to discharge it from the reactor after the reaction is completed, the molecular weight is significantly reduced due to thermal decomposition. In addition, there is a problem that the yield of polydioxanone is reduced when the unreacted monomer is removed by a pulverizer or an extruder after the polymer polymerization. Therefore, in order to solve the process problems caused by the mass production of polydioxanone, a variety of methods have been studied.

[0004] Japanese Patent Publication No. JP2001151878 discloses a method for producing polydioxanone by rapidly cooling the polydioxanone with liquid nitrogen after solid phase polymerization, taking it out of the reactor, freezing and crushing it using a crusher, and passing heated inert gas to remove unreacted monomers. However, in industrial scale-up, it is difficult to extract the polymer by rapid cooling with liquid nitrogen, and there is a problem that the method of removing unreacted monomers is not economical.

[0005] U.S. Patent No. 5,652,331 discloses a method for preparing polydioxanone by liquid phase bulk polymerization. The method maintains the fluidity of the polymer by keeping the temperature higher than the melting point of the polymer, and uses a cyclic anhydride to prevent the reversible reaction of the polymer from causing a decrease in molecular weight. However, the method cannot obtain a high molecular weight polymer, the reaction yield is low, and the monomer residual content of the obtained polymer is high.

[0006] Therefore, it is necessary to develop a preparation method for polydioxanone with low cost, simplified process, mild conditions, satisfactory product performance and the potential to achieve industrial production. Summary of the invention

[0007] In view of the shortcomings of the prior art, the object of the present invention is to provide a novel method for preparing polydioxanone. The method can make the polydioxanone product precipitate from the polymerization system in the form of powder, without the need for dissolution, precipitation and high vacuum desolventization, or freezing and crushing and high vacuum desolventization, thereby avoiding complex and energy-intensive post-processing procedures and the resulting product loss or molecular weight reduction. During the precipitation process of the polymer, part of the unreacted monomer can be removed at the same time to obtain a high molecular weight polymer product with a low monomer content.

[0008] To achieve the object, the present invention provides a method for preparing polydioxanone by solution polymerization, characterized in that under anhydrous and oxygen-free conditions protected by inert gas, ring-opening polymerization of p-dioxanone as a polymerization monomer is carried out in the presence of a catalyst and a solvent to obtain polydioxanone precipitated from the polymerization system in the form of powder.

[0009] Compared with traditional bulk polymerization methods, such as melt polymerization and solid-phase polymerization, this technical method has the advantages of simplified process, mild conditions, easy equipment maintenance, easy post-processing, low cost, and low monomer residual content of the resulting polymer. The product can be used in medical materials, packaging materials, environmental materials and other fields due to its biocompatibility, biodegradability, recyclability, physical and mechanical properties.

[0010] Other features and advantages of the present application will be described in detail in the subsequent detailed description. DETAILED DESCRIPTION

[0011] The specific implementation methods of the present application are described in detail below, but it should be noted that the protection scope of the present application is not limited by these specific implementation methods, but is determined by the claims in the appendix.

[0012] Except for the embodiment section, any specific numerical value disclosed herein (including the endpoint of the numerical range) is not limited to the exact value of the numerical value, but should be understood to also cover values ​​close to the exact value, such as all possible numerical values ​​within the range of ±5% of the exact value. In addition, for the disclosed numerical range, between the endpoint values ​​of the range, between the endpoint value and the specific point value in the range, and between each specific point value can be arbitrarily combined to obtain one or more new numerical ranges, and these new numerical ranges should also be regarded as specifically disclosed herein.

[0013] Unless otherwise specified, the terms used herein have the same meaning as commonly understood by those skilled in the art. If a term is defined herein and its definition is different from the commonly understood meaning in the art, the definition herein shall prevail.

[0014] In this application, except for the contents clearly stated, any matters or items not mentioned are directly applicable to the aspects known in the art without any changes. Moreover, any embodiment described herein can be freely combined with one or more other embodiments described herein, and the technical solutions or technical ideas formed thereby are deemed to be part of the original disclosure or original record of this application, and should not be regarded as new contents not disclosed or anticipated herein, unless a person skilled in the art considers that the combination is obviously unreasonable.

[0015] All patent and non-patent literature, including but not limited to textbooks and journal articles, mentioned herein are incorporated herein by reference in their entirety.

[0016] The term "room temperature" as used herein refers to ambient temperature, for example, a temperature of 20-30°C.

[0017] In one embodiment, the present invention provides a method for preparing polydioxanone by solution polymerization, characterized in that, under anhydrous and oxygen-free conditions protected by inert gas, p-dioxanone is used as a polymerization monomer to undergo a ring-opening polymerization reaction in the presence of a catalyst and an aromatic hydrocarbon solvent to obtain polydioxanone precipitated in the form of powder.

[0018] The solvent used in the embodiments of the present invention is specifically an aromatic hydrocarbon solvent. Other solvents that can also dissolve the catalyst and the polymerization monomer p-dioxanone at the reaction temperature, such as commonly used alcohol solvents such as hexafluoroisopropanol and aliphatic hydrocarbon solvents such as n-hexane, are difficult to form solution polymerization conditions for p-dioxanone. In a preferred embodiment, the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene, o-xylene, m-xylene, p-xylene, and polycyclic aromatic hydrocarbons. In a more preferred embodiment, the aromatic hydrocarbon solvent is toluene.

[0019] The volume ratio between the solvent and the polymerizable monomer used in the embodiment of the present invention is 2:1 to 4:1. If the amount of solvent used is too low, the fluidity of the polymerization system cannot be maintained after cooling; if the amount of solvent used is too high, the polymerization yield is significantly reduced and the intrinsic viscosity of the resulting polymer is reduced. In a preferred embodiment, the volume ratio between the aromatic hydrocarbon solvent and the polymerizable monomer is 2:1 to 3:1. In the most preferred embodiment, the volume ratio between the aromatic hydrocarbon solvent and the polymerizable monomer is 3:1.

[0020] In an embodiment of the present invention, any catalyst capable of catalyzing the ring-opening polymerization of dioxanone may be used, such as stannous octoate, stannous oxalate, dibutyltin oxide, tetrabutyltin, triethylaluminum, aluminum triisopropoxide, zinc lactate, etc. In a preferred embodiment, the catalyst used is selected from any one of stannous octoate, stannous oxalate, dibutyltin oxide, and tetrabutyltin. In a most preferred embodiment, the catalyst used is stannous octoate. In an embodiment of the present invention, the molar ratio between the polymerizable monomer and the catalyst is 100:1 to 100000:1. In a preferred embodiment, the molar ratio between the polymerizable monomer and the catalyst is 2000:1 to 6000:1.

[0021] In an embodiment of the present invention, the ring-opening polymerization of dioxanone is carried out at a temperature of 60 to 130° C. for a period of 12 to 96 hours. In a preferred embodiment, the ring-opening polymerization of dioxanone is carried out at a temperature of 70 to 110° C. for a period of 60 to 84 hours. In a more preferred embodiment, the ring-opening polymerization of dioxanone is carried out at a temperature of 80 to 90° C. for a period of 72 hours.

[0022] The method of the present invention is carried out under anhydrous and oxygen-free conditions under the protection of an inert gas, wherein the inert gas used is selected from nitrogen and argon.

[0023] The method of the present invention allows the polymerization system to cool to room temperature after the ring-opening polymerization reaction is completed to precipitate a polydioxanone product in the form of powder, and then obtains a product from which unreacted monomers have been removed by filtering and vacuum drying. In the post-treatment process, it is not necessary to obtain the product by pulverizing with a pulverizer or granulating with an extruder, thereby avoiding product loss or molecular weight reduction caused thereby; since part of the unreacted monomers can be removed simultaneously during the precipitation of the polymer, an additional dissolution and precipitation step (for example, by additionally adding a solvent and a precipitant) is not required to remove the unreacted monomers in the polymer product, thereby greatly simplifying the process flow of preparation and post-treatment, reducing the production cost, and making large-scale industrial production of polydioxanone possible.

[0024] In another embodiment, the present invention also provides a polydioxanone prepared by the method according to the present invention. The obtained polydioxanone product has an intrinsic viscosity at 30°C of >1.0 dL / g, preferably an intrinsic viscosity of >1.2 dL / g, particularly preferably an intrinsic viscosity of >1.5 dL / g; and a residual monomer content of <0.8%, preferably a residual monomer content of <0.6%, and more preferably a residual monomer content of <0.5%.

[0025] Example

[0026] The present invention is further described in detail below using examples, but the present invention is not limited to these examples.

[0027] The p-dioxanone monomer used was provided by Sinopec Yangzi Petrochemical Co., Ltd. The catalyst was stannous octoate, provided by Alfa Aesar, with a trade name of 2-ethylhexanoic acid tin (II), and the purity of the reagent was 96%. The solvents used were all provided by Anergy, and were dehydrated with molecular sieves before use to control the water content to below 10 ppm.

[0028] The following measurement methods were used in the characterization of the prepared polymers:

[0029] Intrinsic viscosity: measured by an Ubbelohde viscometer at 30°C with hexafluoroisopropanol as solvent and a 0.8 mm three-tube Ubbelohde viscometer.

[0030] Residual monomer content: measured by H NMR spectrum using AVANCEIII HD 600 MHz NMR instrument supplied by Bruker. The sample to be tested was dissolved in deuterated trifluoro acid (CIL) and H NMR spectrum analysis was performed at room temperature.

[0031] Example 1 (comparative)

[0032] In a glove box, add the catalyst stannous octoate (stannous octoate is dissolved in toluene, 0.0031mmol / mL) and the p-dioxanone monomer in a molar ratio of 1:3791 into a sealed tube with a magnetic element, seal the sealed tube, take the sealed tube out of the glove box, stir and react in an 80°C oil bath for 72 hours, and stop stirring the magnetic element after polymerization and viscosity enhancement. After the reaction is completed, turn off the heating, cool to room temperature, and obtain poly-p-dioxanone in the form of a block solid. Hexafluoroisopropanol is added to dissolve the crude product, and then precipitate it in methanol, filter it, and place the filtered poly-p-dioxanone in a vacuum oven to dry to constant weight.

[0033] Embodiment 2-7

[0034] In a glove box, the catalyst stannous octoate (stannous octoate is dissolved in toluene, 0.0031 mmol / mL) and the p-dioxanone monomer are added to a sealed tube with a magnetic element in a molar ratio of 1:3791, and then the solvent toluene is added. The volume ratio of the solvent to the monomer in Examples 2-7 is 2:1, 3:1, 5:1, 7:1, 10:1, and 15:1, respectively. The sealed tube is sealed, taken out of the glove box, and stirred in an 80°C oil bath for 72 hours. After the reaction is completed, the heating is turned off, and the poly-p-dioxanone is cooled to room temperature to precipitate in the form of powder, filtered, and the filtered poly-p-dioxanone is placed in a vacuum oven and dried to constant weight.

[0035] Embodiment 8-15

[0036] In a glove box, add the catalyst stannous octoate (stannous octoate is dissolved in a solvent, 0.0031 mmol / mL) and the p-dioxanone monomer in a molar ratio of 1:3791 to a sealed tube with a magnetic element, and then add the solvent until the volume ratio of the solvent to the monomer is 3:1. The solvents used in Examples 8-15 are benzene, o-xylene, m-xylene, p-xylene, hexafluoroisopropanol, methanol, ethanol, and n-hexane, respectively. Seal the sealed tube, take it out of the glove box, and stir the reaction in an 80°C oil bath for 72 hours. After the reaction is completed, turn off the heating, cool to room temperature, filter, and place the filtered poly-p-dioxanone in a vacuum oven to dry to constant weight.

[0037] Examples 16-22

[0038] In a glove box, the catalyst stannous octoate (stannous octoate is dissolved in toluene, 0.0031 mmol / mL) and the polydioxanone monomer are added to a sealed tube with a magnetic device in a molar ratio of 1:3791, and then the solvent toluene is added to a volume ratio of the solvent to the monomer of 3:1, and the sealed tube is sealed and taken out of the glove box. In Examples 16-22, the reaction is stirred in an oil bath at 60°C, 70°C, 90°C, 100°C, 110°C, 120°C, and 130°C for 72 hours. After the reaction is completed, the heating is turned off, cooled to room temperature, filtered, and the filtered polydioxanone is placed in a vacuum oven and dried to constant weight.

[0039] Examples 23-28

[0040] In a glove box, the catalyst stannous octoate (stannous octoate is dissolved in toluene, 0.0031 mmol / mL) and the polydioxanone monomer are added to a sealed tube with a magnetic device in a molar ratio of 1:3791, and then the solvent toluene is added to a volume ratio of the solvent to the monomer of 3:1, and the sealed tube is sealed and taken out of the glove box. In Examples 23-28, the reaction is stirred in an 80°C oil bath for 12h, 24h, 36h, 48h, 60h, and 84h, respectively. After the reaction is completed, the heating is turned off, cooled to room temperature, filtered, and the filtered polydioxanone is placed in a vacuum oven and dried to constant weight.

[0041] The polymerization conditions used in the above examples and the test results of the yield, intrinsic viscosity, monomer residue and other properties of the obtained products are shown in the following table.

[0042] Table 1 Polymerization conditions and performance test results of Examples 1-28

[0043]

[0044] *Note: Only vacuum stripping and desolvation are performed.

[0045] In Examples 2-3, 8-11, and 16-28, by adopting a solution polymerization method, the crude polydioxanone product is directly precipitated in the form of powder from the polymerization system after cooling, thereby eliminating the post-treatment steps of dissolution and re-precipitation in Comparative Example 1, and significantly reducing the monomer residual content of the product by only vacuum stripping and desolventizing. From the results of Examples 2-3 and Comparative Examples 4-7, it can be seen that as the volume ratio of solvent to monomer increases, the yield and intrinsic viscosity of the polydioxanone product first increase and then decrease, and the monomer residual content decreases. When the volume ratio of solvent to monomer is 3:1, the best combination of yield, intrinsic viscosity and monomer residual content is achieved. In Comparative Examples 4-7, due to the excessive amount of solvent, a high molecular weight polydioxanone product cannot be obtained, and the yield is significantly reduced. In Comparative Examples 12-15, polydioxanone products cannot be obtained because solution polymerization conditions cannot be formed. By adjusting and optimizing the solution polymerization reaction conditions such as the selection of solvent, the volume ratio of solvent to polymerization monomer, reaction temperature, reaction time, etc., a polydioxanone product with high intrinsic viscosity and low monomer residual content can be obtained.

[0046] Although the specific implementations of the present invention have been described in detail above in conjunction with the embodiments, it should be pointed out that the protection scope of the present invention is not limited by these specific implementations, but is determined by the claims. Those skilled in the art may make appropriate changes to these implementations without departing from the technical ideas and purport of the present invention, and these changed implementations are obviously also included in the protection scope of the present invention.

Claims

1. A method for preparing polydioxanone by solution polymerization, characterized in that: Under anhydrous and oxygen-free conditions protected by inert gas, p-dioxanone is used as a polymerization monomer to undergo a ring-opening polymerization reaction in the presence of a catalyst and an aromatic hydrocarbon solvent to obtain poly-p-dioxanone precipitated in the form of powder, wherein the aromatic hydrocarbon solvent is selected from one or more of benzene, toluene, o-xylene, m-xylene, p-xylene, and polycyclic aromatic hydrocarbons, the volume ratio of the aromatic hydrocarbon solvent to the polymerization monomer is 2:1 to 4:1, the catalyst is selected from any one of stannous octoate, stannous oxalate, dibutyltin oxide, and tetrabutyltin, and the ring-opening polymerization reaction is carried out at a temperature of 60 to 130°C.

2. The method according to claim 1, characterized in that The inert gas is selected from nitrogen and argon.

3. The method according to claim 1, characterized in that The volume ratio of the aromatic hydrocarbon solvent to the polymerization monomer is 2:1 to 3:

1.

4. The method according to claim 1, characterized in that: The catalyst is stannous octoate.

5. The method according to claim 1, characterized in that The molar ratio of the polymerizable monomer to the catalyst is 100:1 to 100000:1, preferably 2000:1 to 6000:

1.

6. The method according to claim 1, characterized in that The ring-opening polymerization reaction is carried out at a temperature of preferably 70 to 110°C, more preferably 80 to 90°C.

7. The method according to claim 1, characterized in that The ring-opening polymerization reaction is carried out for 12 to 96 hours, preferably 60 to 84 hours.

8. The method according to claim 1, characterized in that The precipitation is performed by cooling the polymerization system to room temperature after the ring-opening polymerization reaction is completed.

9. The method according to claim 8, characterized in that The method further comprises the steps of filtering and drying the polydioxanone to a constant weight after the polydioxanone is precipitated.

10. Polydioxanone prepared by the method according to any one of claims 1 to 9, characterized in that The intrinsic viscosity at 30°C is >1.0 dL / g, and the residual monomer content is <0.8%.

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