Highly uniform medical grade absorbable polyester, method of preparation and production system

Abstract

The application discloses a kind of high uniformity medical grade absorbable polyester, preparation method and production system, production system includes kettle type closed stirrer, auxiliary tank, three-way valve and closed kettle type reactor;Three-way valve is communicated with kettle type closed stirrer by melt metering pump;It is communicated with auxiliary tank by micro-injection pump;It is communicated with closed kettle type reactor by static mixer;The side inside of three-way valve and micro-injection pump communication side is designed funnel shape, including funnel neck and funnel mouth, the side surface and bottom surface of funnel neck are equipped with uniform small hole.The application discloses a kind of system specially used for preparing high uniformity medical grade absorbable polyester and the preparation method matched therewith, by using special production system again cooperation specific process parameter can successfully prepare with medical grade absorbable polyester, especially suitable for the preparation of poly-l-lactide and polyglycolide with higher viscosity, more difficult to produce, the product obtained has high uniformity, high molecular weight and low monomer residue.

Description

Technical Field

[0001] This invention relates to the technical field of biomedical absorbable polyester synthesis, and particularly to a highly uniform medical-grade absorbable polyester, its preparation method, and its production system. Background Technology

[0002] Absorbable polyesters, represented by polylactic acid and polyglycolic acid, are ideal biomaterials. Due to their good biocompatibility and bioabsorbability, absorbable polyesters are widely used in the research and application of tissue repair materials. Many polyesters have been approved by the U.S. Food and Drug Administration (FDA) for use in the manufacture of Class II and Class III medical devices.

[0003] Due to the higher requirements for sample purity, and the fact that polylactic acid-based unsaturated polyesters are prone to generating more side reactions during melt polymerization, medical-grade absorbable polyesters are generally prepared using low-temperature bulk polymerization technology. Furthermore, the demand for medical-grade absorbable polyesters is even lower, and industrial production typically employs batch reactors. Based on these circumstances, uniformity issues easily arise during the preparation of medical-grade absorbable polyesters, mainly for the following reasons: First, the reaction temperature is relatively low, causing the polymer viscosity to continuously rise and solidify in the early stages of the reaction. Combined with the large amount of heat released during the reaction, this results in a significant temperature gradient within the polymer due to insufficient heat dissipation, affecting the polymerization effect. Second, the high viscosity of the polymer in the early stages of the reaction greatly reduces the stirring effect, severely impacting the dispersion of catalysts, initiators, and other auxiliaries, leading to uneven local reactions within the polymer. Third, monomers volatilize during the melting process, and these volatilized monomers re-condense at the top of the reactor, resulting in fewer monomers actually participating in the reaction, causing a significant discrepancy between the polymerization results and the theoretical values. The above problems are even more pronounced in the polyglycolic acid system. When preparing polyglycolic acid, the viscosity of the polymer often rises rapidly and turns into a solid within the first few minutes of the reaction. The inability to dissipate heat and the uneven local reaction will directly lead to polymerization failure.

[0004] EP1468035B1 and US6706854B2 utilize reaction systems with a large reactor connected in series with multiple smaller reactors. The monomers, catalyst, and initiator are first added to the large reactor for heating and stirring. After stirring for a certain period, the blended melt is pumped into the multiple smaller reactors for a prolonged reaction. While this method effectively addresses the temperature gradient issue, the overall melt viscosity increases because the monomers have already reacted during heating and stirring in the large reactor. This makes it difficult to ensure complete dispersion of catalysts, initiators, and other additives, thus failing to address the problem of poor product uniformity. Furthermore, the higher melt viscosity can cause residues to remain on the pipe walls during entry into the smaller reactors, leading to blockages. Finally, the lack of a dispersion device in the parallel smaller reactors allows high molecular weight components to continuously settle during the long reaction period, resulting in poor reaction efficiency and high intrinsic viscosity dispersion.

[0005] Chinese patent document CN 113166378 A discloses a method for preparing granular or powdered reabsorbable polyester via bulk polymerization. This method employs a layered addition of additives to improve polymerization efficiency, showing a significant improvement compared to a one-time direct addition. However, the technical solution specifies a suitable container volume of 1 to 2 L. For large-scale production, multiple containers, possibly 10 to 20, would be used. This clearly implies that the method is not suitable for larger reactor volumes. It can be reasonably inferred that larger volumes would still lead to limited heat release and uneven local reaction. Furthermore, data from Example 1 of this technical solution reveals that in preparing high molecular weight polylactide, viscosity differences still exist between products in the reaction vessel, and the residual monomer concentration at the top of the reaction flask is significantly higher than at the bottom, indicating that the dispersion effect of the additives still needs improvement. This phenomenon would become more pronounced if the container volume were further increased.

[0006] Chinese patent document with application publication number CN111346579 A discloses a polylactic acid polymerization reaction apparatus and system. The system continuously circulates the melt in a static mixer to improve the mixing effect. However, the reaction temperature of this method must be above the melting point of the polymer. Higher reaction temperatures will significantly increase the degree of side reactions. Therefore, an efficient composite stabilizer must be added to ensure the reaction effect. More additives and by-products are completely unsuitable for the production of medical-grade polylactic acid. Summary of the Invention

[0007] To address the aforementioned problems in the existing technology, this invention discloses a system and a corresponding preparation method specifically for preparing highly uniform medical-grade absorbable polyester. By employing a special production system and specific process parameters, medical-grade absorbable polyester can be successfully prepared. It is particularly suitable for the preparation of polylactide and polyglycolic acid, which have higher viscosity and are more difficult to produce. The prepared product has high uniformity, high molecular weight, and low monomer residue.

[0008] The specific technical solution is as follows:

[0009] A system for preparing highly uniform medical-grade absorbable polyester includes a closed-type stirrer, an auxiliary agent tank, a three-way valve, and a closed-type reactor.

[0010] The three-way valve is connected to the closed-type agitator via a melt metering pump.

[0011] The three-way valve is connected to the auxiliary agent container via a micro-injection pump;

[0012] The three-way valve is connected to the closed-loop reactor via a static mixer;

[0013] The three-way valve is designed in a funnel shape on the side connected to the micro-injection pump, including a funnel neck and a funnel opening. The side and bottom of the funnel neck are provided with uniform small holes.

[0014] The preparation system disclosed in this invention includes a closed-loop stirrer for separately storing monomers, an auxiliary agent tank for separately storing auxiliary agents, and a closed-loop reactor for reacting the two. More importantly, it employs a three-way valve with a special structure. The side of the valve connected to the auxiliary agent tank is designed as a funnel, with uniform small holes on the side and bottom of the funnel neck. Furthermore, in conjunction with the preparation process, the melt and auxiliary agent solution are thoroughly mixed at an appropriate flow rate, thereby achieving a good dispersion effect of the auxiliary agent within the polymer and reducing the internal temperature gradient during the polymer reaction. This results in the preparation of a highly uniform medical-grade absorbable polyester, with a significant improvement in performance, especially when preparing polyesters with high viscosity such as polylactide and polyglycolic acid.

[0015] Preferred:

[0016] The diameter of the funnel neck is selected from 0.25 to 1.5 mm, and the maximum diameter of the funnel opening is 3 to 6 times the diameter of the funnel neck;

[0017] The diameter of the small holes provided on the side and bottom of the funnel neck is 5 to 40% of the diameter of the funnel neck;

[0018] The height of the bottom surface of the funnel neck from the bottom of the three-way valve is 25-45% of the inner diameter of the three-way valve.

[0019] The above parameter design can ensure thorough mixing of the melt and the additive solution.

[0020] Preferred:

[0021] The closed-loop reactor can be one unit or N units connected in parallel, where N≤10;

[0022] The volume of a single closed-loop reactor is 1 to 10 L.

[0023] When the production capacity is large, multiple parallel closed-type reactors can be used to meet the production needs. Moreover, experiments have shown that even after the production capacity is expanded, the product still has high intrinsic viscosity, good uniformity and low monomer residue.

[0024] This invention also discloses a method for preparing highly uniform medical-grade absorbable polyester, used in conjunction with the above-mentioned production system. The specific preparation method is as follows:

[0025] S1: Open all valves to replace the entire system with an inert gas atmosphere and continuously purge with inert gas;

[0026] S2: Under an inert gas atmosphere, the reaction monomer and inorganic sodium salt are added to the closed stirrer and heated to melt. The resulting melt is then fed into a melt metering pump and then into a three-way valve.

[0027] S3: The catalyst, initiator and organic solvent are mixed evenly to obtain an auxiliary agent solution. The auxiliary agent solution is injected into the auxiliary agent tank and then introduced into a three-way valve through a micro-injection pump.

[0028] S4: In the three-way valve, the melt and the additive solution are fully mixed at an appropriate flow rate and then introduced into the static mixer. After further homogenization, it is introduced into the closed autoclave reactor. After all the materials have entered, the reactor is heated to carry out the polymerization reaction to obtain a highly uniform medical-grade absorbable polyester.

[0029] The speed of the melt metering pump is 0.5 to 3.0 L / min, and the speed of the micro-injection pump is 1 to 10‰ of the speed of the melt metering pump.

[0030] The preparation method disclosed in this invention is used in conjunction with the aforementioned production system. By utilizing the special structure of the production system and the precise control of process parameters in this preparation method, it is possible to ensure the preparation of medical-grade absorbable polyester with high uniformity.

[0031] Experiments have shown that mismatched speeds between the melt metering pump and the micro-injection pump can lead to a significant decrease in product uniformity, a decrease in intrinsic viscosity, and a substantial increase in monomer residue. In severe cases, it can even cause blockage of the injection pump pipeline and reaction failure.

[0032] In step S1, the inert gas is high-purity nitrogen and / or high-purity argon, preferably high-purity argon.

[0033] In step S2:

[0034] The reaction monomers are selected from one or more of the following: L-lactide, D-lactide, racemic lactide, glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and lactam.

[0035] The inorganic sodium salt is selected from sodium chloride and / or sodium carbonate;

[0036] Experiments have shown that the addition of the inorganic sodium salt can reduce the amount of volatilization of the reactants in the closed stirrer, thereby ensuring the polymerization quality of the final product.

[0037] Preferably, the mass of the inorganic sodium salt is 0.01 to 5.00 wt% of the mass of the reactant monomer; more preferably, it is 0.01 to 0.5 wt%.

[0038] Preferably, in step S2:

[0039] After adding the reactant monomer and inorganic sodium salt to a closed stirrer, the vacuum was first evacuated to a vacuum level of -0.1 MPa, and then an inert gas was introduced to reach atmospheric pressure before heating and melting.

[0040] The heating and melting temperature depends on the melting point of the reactant monomer; it is sufficient to heat the reactant monomer to form a melt. Preferably, the heating and melting temperature is 0 to 30°C higher than the melting point of the monomer, and more preferably 5 to 20°C higher.

[0041] Experiments have shown that maintaining a vacuum level of -0.1 MPa is crucial. If the vacuum level is not reached, the intrinsic viscosity of the product will decrease and its uniformity will deteriorate.

[0042] Preferably, the stirring speed in the sealed agitator is 50–500 rpm; more preferably, it is 100–300 rpm. The stirring time after the monomer melts is preferably 10–100 min, more preferably 20–40 min.

[0043] In step S3:

[0044] The catalyst is selected from conventional catalysts for the preparation of polyesters, such as one or more of tin compounds, zinc compounds, antimony compounds, and basic organic catalysts;

[0045] Specifically, it includes stannous chloride, stannous oxide, stannous fluoride, tetraphenyltin, stannous octoate, stannous acetate, stannous stearate, zinc oxide, zinc lactate, zinc stearate, zinc chloride, antimony trioxide, antimony trifluoride, DBU, TBD, etc.; preferably tin compounds, more preferably stannous octoate.

[0046] The amount of catalyst added is 10 to 500 ppm, preferably 10 to 20 ppm, based on the mass of the reactant monomer.

[0047] The initiator is selected from polyols and / or polyacids. The polyols are selected from alcohols with 1 to 15 carbon atoms and 1 to 15 hydroxyl groups, and the molecular structure can be straight-chain, branched, or star-shaped. The polyacids are selected from acids with 1 to 15 carbon atoms and 1 to 15 carboxyl groups, and the molecular structure can be straight-chain, branched, or star-shaped.

[0048] The amount of initiator added is 30 to 5000 ppm, preferably 35 to 500 ppm, based on the mass of the reactant monomer.

[0049] The organic solvent is selected from one or more of toluene, xylene, dimethyl sulfoxide, dichloromethane, and chloroform; preferably toluene.

[0050] The concentration of the auxiliary agent in the solution is 0.005–0.25 g / mL; preferably 0.01–0.15 g / mL.

[0051] In this invention, the concentration of the auxiliary agent is the total concentration of the catalyst and the initiator.

[0052] The water content of the catalyst, initiator, and solvent must be less than 10 ppm. In this preparation method, the specific requirements for the anhydrous and oxygen-free atmosphere are water content < 0.1 ppm and oxygen content < 0.1 ppm. The syringe must be stored in an anhydrous and oxygen-free atmosphere for more than 24 hours in advance to replace the internal air.

[0053] In step S3:

[0054] The auxiliary agent container is under a slightly positive pressure, with the pressure value selected from 0.1 to 1.0 MPa; preferably 0.1 to 0.3 MPa.

[0055] Experiments have shown that maintaining a slightly positive pressure during injection, relative to a pressure of 0 inside the auxiliary agent container, can improve the uniformity of the product.

[0056] In step S4:

[0057] The closed reactor is equipped with a magnetic stirrer with a stirring speed of 100-700 rpm; the specific stirring speed depends on the type of reactant, and is preferably 100-300 rpm.

[0058] The temperature and time of the polymerization reaction are adjusted according to the type of monomer used.

[0059] For lactide, the preferred reaction temperature is 100–160°C, more preferably 120–140°C; for glycolide, the preferred reaction temperature is 120–200°C, more preferably 140–180°C; for ε-caprolactone, the preferred reaction temperature is 80–150°C, more preferably 100–120°C; for blends of lactide and trimethylene carbonate, the preferred reaction temperature is 100–160°C, more preferably 110–130°C; for blends of lactide and glycolide, the preferred reaction temperature is 110–170°C, more preferably 120–150°C; for blends of lactide and ε-caprolactone, the preferred reaction temperature is 80–160°C, more preferably 110–130°C. The reaction time can be adjusted adaptively according to the type of reactant monomer.

[0060] The present invention also discloses a highly uniform medical-grade absorbable polyester prepared according to the above method.

[0061] Compared with the prior art, the present invention has the following advantages:

[0062] This invention discloses a system and a method for preparing highly uniform medical-grade absorbable polyester. By using a special production system and specific process parameters, medical-grade absorbable polyester can be successfully prepared. It is especially suitable for the preparation of polylactide and polyglycolic acid, which have higher viscosity and are more difficult to produce. The prepared product has high uniformity, high molecular weight and low monomer residue. Attached Figure Description

[0063] Figure 1 This invention discloses a system for preparing highly uniform medical-grade absorbable polyester.

[0064] Figure 2 This is a schematic diagram of the structure of a three-way valve;

[0065] Figure 3 This is a schematic diagram of the funnel neck in a three-way valve;

[0066] Figure 4 The preparation system used in Comparative Example 3;

[0067] In the diagram, 1-sealed agitator, 2-transfer pipeline, 3-melt metering pump, 4-additive tank, 5-micro injection pump, 6-three-way valve, 7-static mixer, 8-sealed batch reactor;

[0068] 101-Agitator cover, 102-Agitator body, 103-Mechanical stirring motor, 104-Mechanical stirring blade, 105-Agitator air inlet, 106-Agitator vacuum port, 107-Temperature sensor, 108-Vacuum gauge, 109-Sealing flange bolt, 110-Agitator discharge valve;

[0069] 401 - Additive tank body, 402 - Additive tank air inlet, 403 - Additive tank vacuum port, 404 - Additive tank rubber stopper, 405 - Syringe, 406 - Additive tank discharge valve;

[0070] 601 - Funnel neck, 602 - Funnel opening;

[0071] 801-Reaction vessel body, 802-Reaction vessel top cover, 803-Magnetic stirring motor, 804-Magnetic stirring blade, 805-Sealing flange bolts, 806-Reaction vessel feed valve. Detailed Implementation

[0072] To further understand the present invention, the present invention will be specifically described below with reference to the embodiments and accompanying drawings. However, the present invention is not limited to these embodiments. Non-essential improvements and adjustments made by those skilled in the art under the core guiding principles of the present invention are still within the protection scope of the present invention.

[0073] The system for preparing highly uniform medical-grade absorbable polyester disclosed in this invention is as follows: Figure 1 As shown, it includes a closed-type agitator 1, an additive tank 4, a three-way valve 6, and a closed-type reactor 8; the three-way valve 6 is connected to the closed-type agitator 1 through a melt metering pump 3; it is connected to the additive tank 4 through a micro-injection pump 5; and it is also connected to the closed-type reactor 8 through a static mixer 7; the various devices are connected by a conveying pipeline 2.

[0074] The sealed stirred tank reactor (hereinafter referred to as the stirred tank) 1 includes a stirred tank cover 101, sealing flange bolts 109, stirred tank body 102, stirred tank air inlet 105, stirred tank vacuum port 106, mechanical stirrer (including mechanical stirring motor 103 and mechanical stirring blades 104), heating device, and discharge port; during operation, the reactants are directly added into the tank body 102, and then the cover 101 and the tank body 102 are fixed with sealing flange bolts 109 to seal the reactor; the tank body 102 is a three-layer jacket. The structure comprises an inner wall, a heating jacket, and an insulation layer. An air inlet 105 is located at the top of the upper cover 101 for connecting to an inert gas. A vacuum port 106 is located at the top of the upper cover 101 for connecting to a vacuum pump. A mechanical stirrer is located at the center of the top of the upper cover for stirring the reactants. The heating device is an electric heating jacket located in the middle layer of the vessel body for heating the reactants. The discharge port is located at the bottom of the vessel body 102 for discharging the material inside the vessel; the discharge and cessation of material discharge are controlled by the discharge valve 110. The volume of the stirred vessel 1 is preferably 1–50 L, more preferably 5–40 L, and even more preferably 10–30 L.

[0075] The inlet of the melt metering pump 3 is connected to the outlet of the stirred tank 1, and the outlet is connected to the three-way valve 6 for timed, quantitative, and speed delivery of the reaction monomers.

[0076] The additive tank 4 includes a tank body 401, an inlet, an outlet, an air inlet 402, and a vacuum port 403. It is used to store an additive solution obtained by mixing reaction aids such as catalysts and initiators with a solvent. The inlet is used to add the additive solution and can be sealed with a rubber stopper 404 during use. Addition is performed using a syringe 405. The outlet is connected to a micro-injection pump, and the output and stop of the additive solution are controlled by the additive tank outlet valve 406. The air inlet 402 is used to connect to an inert gas. The vacuum port 403 is used to connect to a vacuum device. The inlet of the additive tank is sealed with multiple layers of rubber stoppers to ensure that the oxygen and water content inside the tank is below 0.1 ppm when adding the additive solution. The volume of the additive tank is preferably 5–100 mL, more preferably 10–50 mL.

[0077] The outlet of the micro-injection pump 5 is connected to a three-way valve 6, and the inlet is connected to an auxiliary agent tank 4, for timed, quantitative, and speed delivery of the auxiliary agent solution.

[0078] The inlet of the static mixer 7 is connected to the three-way valve 6, and the outlet is connected to the inlet of the reactor 8, for further homogenization of the additives and reactants system.

[0079] The closed-loop reactor (hereinafter referred to as the reactor vessel) 8 includes a reactor vessel body 801, a reactor vessel cover 802, a magnetic stirrer (including a magnetic stirring motor 803 and magnetic stirring blades 804), sealing flange bolts 805, and a feed inlet. The reactor vessel body 801 and the cover 802 are sealed and fixed together by the sealing flange bolts 805. The feed inlet is connected to the discharge port of the static mixer 7 and is controlled by the reactor vessel feed valve 806. The number of reactor vessels 8 can be one or N (N≤10). The volume of a single reactor vessel 8 is preferably 1 to 10 L. When it is necessary to increase the production capacity, multiple reactor vessels can be connected in parallel. The closed-loop reactor can be cylindrical or a conical structure with a certain taper.

[0080] In this invention, the three-way valve 6 adopts a special structural design, such as... Figure 2 and 3 As shown, the internal design of the side of the three-way valve 6 connected to the micro-injection pump 4 is funnel-shaped, while the other two sides (the sides connected to the melt metering pump 3 and the static mixer 7) have a conventional design. The funnel-shaped design includes a funnel neck 601 and a funnel opening 602. The funnel neck 601 is cylindrical, with uniformly distributed small holes on its sides and bottom. The diameter d1 of the funnel neck 601 is selected from 0.25 to 1.5 mm. The maximum diameter d2 of the funnel opening 602 is 3 to 6 times that of d1. The diameter d3 of the small holes on the sides and bottom is 5 to 40% of d1. The height h of the bottom surface of the funnel neck 601 from the bottom of the three-way valve is 25 to 45% of the inner diameter D of the three-way valve. This special design ensures that the additives enter the interior of the molten monomer as uniformly as possible.

[0081] Example 1

[0082] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0083] (2) Weigh 5 kg of L-lactide and 3 g of sodium chloride, and add them to a stirred tank (8 L in volume) in flowing nitrogen. Secure the top cover of the stirred tank with a flange. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75°C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105°C and stir at 200 rpm for 30 minutes.

[0084] (3) Take 10 ppm (0.05 g) of stannous octoate and 200 ppm (1.00 g) of ethylene glycol in a vacuum glove box. Then add the two solutions to 15 mL of ultra-dry toluene and stir until completely mixed. Then draw the mixture into a syringe. Take the syringe out of the glove box and quickly insert it into the rubber stopper of the auxiliary agent container. During the injection, the auxiliary agent container is under a slight positive pressure of 0.2 MPa.

[0085] (4) Open the valves of each vessel and tank, turn on the magnetic stirrer of the reactor (8L volume), set the stirring speed to 250rpm, turn on the melt metering pump and the micro-injection pump, set the speed of the melt metering pump to 2.5L / min and the speed of the micro-injection pump to 8mL / min; the melt and the additive solution enter the three-way valve at the above speeds, and then enter the reactor after passing through the static mixer. After all the materials have entered the reactor, close the reactor valve, heat the reactor temperature to 120℃, and start the reaction for 5 days;

[0086] (5) After the reaction is complete, unscrew the flange and open the reactor lid. Take out the whole product and divide it into three parts: upper, middle and lower. Crush each part into small pieces. Take appropriate amounts of product samples from the crushed upper, middle and lower parts to test their intrinsic viscosity, and list them in Table 1 below. The monomer residue of each part is measured by gas chromatography, and the mass percentage of monomer residue is listed in Table 1 below, which is recorded as monomer residue (before extraction). Then, place the product samples from the upper, middle and lower parts into supercritical carbon dioxide for extraction. The monomer residue after extraction is also measured by gas chromatography, and the values ​​are also listed in Table 1, which is recorded as monomer residue (after extraction).

[0087] Table 1

[0088] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.11 4.11 4.12 Monomer residue (before extraction) 2.80wt% 2.75wt% 2.81wt% Monomer residue (after extraction) 0.43wt% 0.42wt% 0.43wt%

[0089] Three parallel tests were conducted on the product sample from the upper part, and its intrinsic viscosity (IV) data were measured respectively. The first, second and third data were 4.10, 4.11 and 4.10 dL / g, respectively.

[0090] Comparative Example 1

[0091] The preparation process and production system used are basically the same as those in Example 1, except that the specially designed funnel-shaped three-way valve is replaced with an ordinary three-way valve.

[0092] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the comparative example were obtained and are listed in Table 2 below.

[0093] Table 2

[0094] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.18 4.05 4.11 Monomer residue (before extraction) 2.85wt% 2.91wt% 2.77wt% Monomer residue (after extraction) 0.39wt% 0.42wt% 0.40wt%

[0095] Comparative Example 2

[0096] The preparation process and production system used are basically the same as those in Example 1, except that the funnel-shaped three-way valve does not have a small hole on the side of the funnel neck, so the solution can only flow out from the bottom.

[0097] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the comparative example were obtained and are listed in Table 3 below.

[0098] Table 3

[0099] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.05 3.80 4.13 Monomer residue (before extraction) 2.10wt% 2.36wt% 2.76wt% Monomer residue (after extraction) 0.44wt% 0.46wt% 0.43wt%

[0100] Comparing Tables 1-3, compared with the data of Example 1, the intrinsic viscosity of the products prepared by Comparative Examples 1 and 2 is slightly lower, the uniformity is poorer, and the monomer residue is unstable. This indicates that the funnel-type three-way valve design of the present invention can improve the uniformity of the reaction system, thereby improving the polymerization quality.

[0101] Comparative Example 3

[0102] The production system used in this comparative example is as follows: Figure 4 As shown.

[0103] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0104] (2) Weigh 5 kg of L-lactide, 3 g of sodium chloride, 10 ppm (0.05 g) of stannous octoate and 200 ppm (1.00 g) of ethylene glycol, and add them to a stirred tank (8 L volume) under flowing nitrogen. Secure the top of the stirred tank with a flange. To ensure uniform dispersion of the catalyst and initiator, add 2.5 kg of L-lactide first, followed by the initiator, catalyst and sodium chloride, and finally add the remaining 2.5 kg of L-lactide. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75°C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105°C and stir at 200 rpm for 30 minutes.

[0105] (3) Open the valves of each vessel and tank, turn on the magnetic stirrer of the reactor (8L volume), set the stirring speed to 250rpm, turn on the melt metering pump and the micro-injection pump, set the speed of the melt metering pump to 2.5L / min, the melt enters the reactor after passing through the static mixer, and after all the material has entered the reactor, close the reactor valve, heat the reactor temperature to 120℃, and start the reaction for 5 days;

[0106] (5) After the reaction is complete, unscrew the flange and open the top cover of the reactor. Take out the whole product and divide it into three parts: upper, middle and lower. Crush each part into small pieces. Take appropriate amounts of product samples from the crushed upper, middle and lower parts to test their intrinsic viscosity and monomer residue before and after extraction. The results are listed in Table 4 below.

[0107] Table 4

[0108] upper part Central lower part Intrinsic viscosity (IV) / dL / g 3.67 3.98 3.87 Monomer residue (before extraction) 13.75 3.88％ 5.17％ Monomer residue (after extraction) 0.41％ 0.43％ 0.40％

[0109] Comparing the data in Tables 1 and 4, it can be seen that the intrinsic viscosity, uniformity, and monomer residue of this comparative example are all worse than those of Example 1, indicating that the design of the additive tank and the special processing method provided in this invention can significantly improve the polymerization quality.

[0110] Comparative Example 4

[0111] The preparation process is basically the same as that in Example 1, except that in step (3), the pressure inside the auxiliary agent container is 0 during the injection process.

[0112] The same test method as in Example 1 was used, but only the intrinsic viscosity of the upper sample was tested in three parallel tests, and its intrinsic viscosity (IV) data were measured. The first, second and third data were 4.07, 4.11 and 3.98 dL / g, respectively.

[0113] Compared with the results of three parallel experiments in Example 1, the uniformity of this comparative example is slightly worse. This indicates that maintaining a slight positive pressure during injection can improve the polymerization quality in this invention.

[0114] Comparative Example 5

[0115] The preparation process is basically the same as that in Example 1, except that in step (2), the vacuum is evacuated to a vacuum level of -0.05MPa.

[0116] The same test method as in Example 1 was used, but only the intrinsic viscosity (IV) data of the upper, middle and lower parts of the product sample were tested. The data for the upper, middle and lower parts were 3.84, 3.82 and 4.00 dL / g, respectively.

[0117] Comparing the data results with those of Example 1, it can be seen that the intrinsic viscosity of the product prepared in this comparative example decreased and its uniformity deteriorated. This indicates that maintaining a suitable vacuum level in step (2) of this invention can improve the polymerization quality.

[0118] Example 2

[0119] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0120] (2) Weigh 4 kg of D-lactide and 5 g of sodium chloride, and add them to a stirred tank (8 L in volume) in flowing nitrogen. Secure the top cover of the stirred tank with a flange. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75°C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105°C and stir at 200 rpm for 30 minutes.

[0121] (3) Take 20 ppm (0.08 g) of stannous octoate and 200 ppm (0.88 g) of ethylene glycol in a vacuum glove box. Then add the two solutions to 10 mL of ultra-dry toluene and stir until completely mixed. Then draw the mixture into a syringe. Take the syringe out of the glove box and quickly insert it into the rubber stopper of the auxiliary agent container. During the injection, the auxiliary agent container is under a slight positive pressure of 0.2 MPa.

[0122] (4) Open the valves of each vessel and tank, turn on the magnetic stirrer of the reactor (8L volume), set the stirring speed to 250rpm, turn on the melt metering pump and the micro-injection pump, set the speed of the melt metering pump to 2.0L / min and the speed of the micro-injection pump to 5mL / min; the melt and the additive solution enter the three-way valve at the above speeds, and then enter the reactor after passing through the static mixer. After all the materials have entered the reactor, close the reactor valve, heat the reactor temperature to 120℃, and start the reaction for 5 days;

[0123] (5) After the reaction is complete, unscrew the flange and open the reactor lid. Take out the whole product and divide it into three parts: upper, middle and lower. Use tools to crush the product into small pieces. Use the same test method as in Example 1, but only test the intrinsic viscosity (IV) data of the upper, middle and lower product samples. The data for the upper, middle and lower parts are 4.12, 4.11 and 4.11 dL / g, respectively.

[0124] After the experiment, the stirred tank was opened, and the residual monomer (monomer residue from the melting stage and before the polymerization reaction) at the top of the tank was scraped and collected. The weight was 1.952g, and the residual rate was 0.049%.

[0125] Comparative Example 6

[0126] The preparation process is basically the same as in Example 2, except that sodium chloride is not added in step (2).

[0127] The same test method as in Example 1 was used, but only the intrinsic viscosity (IV) data of the upper, middle and lower parts of the product sample were tested. The data for the upper, middle and lower parts were 4.10, 3.82 and 3.83 dL / g, respectively.

[0128] After the experiment, the stirred tank was opened, and the residual monomer at the top of the tank was scraped off and weighed, which was 25.106g, with a residual rate of 6.28%.

[0129] Compared to Example 2, the intrinsic viscosity of the product prepared in this comparative example is slightly lower, the uniformity is worse, and the monomer residue rate before polymerization is significantly higher. This indicates that the addition of inorganic sodium salt in this invention can reduce monomer volatilization and improve the final polymerization quality.

[0130] Example 3

[0131] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0132] (2) Weigh 2 kg of D,L-lactide and 1 g of sodium chloride, and add them to a 3 L stirred tank in flowing nitrogen. Secure the top cover of the stirred tank with a flange. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75 °C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105 °C and stir at 200 rpm for 30 minutes.

[0133] (3) Take 15 ppm (0.03 g) of stannous octoate and 200 ppm (0.40 g) of ethylene glycol in a vacuum glove box. Then add the two solutions to 20 mL of ultra-dry toluene and stir until completely mixed. Then draw the mixture into a syringe. Take the syringe out of the glove box and quickly insert it into the rubber stopper of the auxiliary agent container. During the injection, the auxiliary agent container is under a slight positive pressure of 0.2 MPa.

[0134] (4) Open the valves of each vessel and tank, turn on the magnetic stirrer of the reactor (volume 3L), set the stirring speed to 250rpm, turn on the melt metering pump and the micro-injection pump, set the speed of the melt metering pump to 0.5L / min and the speed of the micro-injection pump to 5mL / min; the melt and the additive solution enter the three-way valve at the above speeds, and then enter the reactor after passing through the static mixer. After all the materials have entered the reactor, close the reactor valve, heat the reactor temperature to 120℃, and start the reaction for 5 days;

[0135] (5) After the reaction is complete, unscrew the flange and open the top cover of the reactor. Take out the whole product and divide it into three equal parts: upper, middle and lower. Crush each part into small pieces.

[0136] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the sample in this example were obtained and are listed in Table 5 below.

[0137] Table 5

[0138] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.15 4.15 4.15 Monomer residue (before extraction) 2.12wt% 2.25wt% 2.19wt% Monomer residue (after extraction) 0.41wt% 0.45wt% 0.44wt%

[0139] Example 4

[0140] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0141] (2) Weigh 6 kg of L-lactide and 2.0 g of sodium chloride, and add them to a stirred tank (8 L in volume) in flowing nitrogen. Secure the top cover of the stirred tank with a flange. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75°C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105°C and stir at 200 rpm for 30 minutes.

[0142] (3) Take 10 ppm (0.06 g) of stannous octoate and 35 ppm (0.21 g) of ethylene glycol in a vacuum glove box. Then add the two solutions to 6 mL of ultra-dry toluene and stir until completely mixed. Then draw the mixture into a syringe. Take the syringe out of the glove box and quickly insert it into the rubber stopper of the auxiliary agent container. During the injection, the auxiliary agent container is under a slight positive pressure of 0.2 MPa.

[0143] (4) Open the valves of each vessel and tank, turn on the magnetic stirrer of the reactor (8L volume), set the stirring speed to 250rpm, turn on the melt metering pump and the micro-injection pump, set the speed of the melt metering pump to 1L / min and the speed of the micro-injection pump to 1mL / min; the melt and the additive solution enter the three-way valve at the above speeds, and then enter the reactor after passing through the static mixer. After all the materials have entered the reactor, close the reactor valve, heat the reactor temperature to 120℃, and start the reaction for 7 days;

[0144] (5) After the reaction is complete, unscrew the flange and open the top cover of the reactor. Take out the whole product and divide it into three equal parts: upper, middle and lower. Crush each part into small pieces.

[0145] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the sample in this example were obtained and are listed in Table 6 below.

[0146] Table 6

[0147] upper part Central lower part Intrinsic viscosity (IV) / dL / g 5.24 5.26 5.25 Monomer residue (before extraction) 2.56wt% 2.54wt% 2.50wt% Monomer residue (after extraction) 0.49wt% 0.50wt% 0.48wt%

[0148] Example 5

[0149] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0150] (2) Weigh 1.31 kg L-lactide, 0.19 kg glycolide and 1.5 g sodium chloride, and add them to a 3 L stirred tank in flowing nitrogen. Secure the top cover of the stirred tank with a flange. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75 °C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105 °C and stir at 200 rpm for 30 minutes.

[0151] (3) Take 10 ppm (0.015 g) of stannous octoate and 400 ppm (0.60 g) of ethylene glycol in a vacuum glove box. Then add the two solutions to 6 mL of ultra-dry toluene and stir until completely mixed. Then draw the mixture into a syringe. Take the syringe out of the glove box and quickly insert it into the rubber stopper of the auxiliary agent container. During the injection, the auxiliary agent container is under a slight positive pressure of 0.2 MPa.

[0152] (4) Open the valves of each vessel and tank, turn on the magnetic stirrer of the reactor (volume 3L), set the stirring speed to 250rpm, turn on the melt metering pump and the micro-injection pump, set the speed of the melt metering pump to 1L / min and the speed of the micro-injection pump to 4mL / min; the melt and the additive solution enter the three-way valve at the above speeds, and then enter the reactor after passing through the static mixer. After all the materials have entered the reactor, close the reactor valve, heat the reactor temperature to 130℃, and start the reaction for 6 days;

[0153] (5) After the reaction is complete, unscrew the flange and open the top cover of the reactor. Take out the whole product and divide it into three parts: upper, middle and lower. Use tools to crush the product into small pieces.

[0154] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the sample in this example were obtained and are listed in Table 7 below.

[0155] Table 7

[0156] upper part Central lower part Intrinsic viscosity (IV) / dL / g 2.51 2.53 2.52 Monomer residue (before extraction) 2.22wt% 2.10wt% 2.45wt% Monomer residue (after extraction) 0.31wt% 0.31wt% 0.32wt%

[0157] Comparative Examples 8-10

[0158] The preparation process is basically the same as in Example 5, except that in step (4), the speed of the micro-injection pump is replaced with 0.5 mL / min, 20 mL / min and 25 mL / min in sequence.

[0159] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the samples of Comparative Examples 8-9 were obtained and are listed in Table 8 below.

[0160] In Comparative Example 10, the syringe pump tubing became blocked, and the reaction failed.

[0161] Table 8

[0162]

[0163] Comparing Example 5 with Comparative Examples 8-10, it can be found that matching the speeds of the melt metering pump and the micro-injection pump is necessary to ensure that the prepared product has a high molecular weight and excellent uniformity.

[0164] Example 6

[0165] (1) Replace the entire system with a nitrogen atmosphere and purge it continuously with nitrogen;

[0166] (2) Weigh 30 kg of L-lactide and 15 g of sodium chloride, and add them to a 50 L stirred tank in flowing nitrogen. Secure the top cover of the stirred tank with a flange. Turn on the mechanical stirrer and adjust the speed to 200 rpm. Turn on the heater of the stirred tank and set the temperature to 75 °C. Open the vacuum port and vacuum device and continue to evacuate for 3 hours, maintaining a vacuum of -0.1 MPa. Close the vacuum port and introduce high-purity nitrogen. After reaching atmospheric pressure, close the inlet. Then raise the temperature to 105 °C and stir at 200 rpm for 30 minutes.

[0167] (3) Take 10 ppm (0.3 g) of stannous octoate and 200 ppm (6.00 g) of ethylene glycol in a vacuum glove box. Then add the two solutions to 140 mL of ultra-dry toluene and stir until completely mixed. Then draw the mixture into a syringe. Take the syringe out of the glove box and quickly insert it into the rubber stopper of the auxiliary agent container. During the injection, the auxiliary agent container is under a slight positive pressure of 0.2 MPa.

[0168] (4) Open the valves of each vessel and turn on the magnetic stirrer of the reactor (there are 4 reactors in parallel, each with a volume of 10L). Set the stirring speed to 250rpm. Turn on the melt metering pump and the micro-injection pump. Set the speed of the melt metering pump to 3L / min and the speed of the micro-injection pump to 14mL / min. The melt and the additive solution enter the three-way valve at the above speeds, and then enter the reactor after passing through the static mixer. After all the materials have entered the reactor, close the reactor valve and heat the reactor temperature to 120℃. Start the reaction for 5 days.

[0169] (5) After the reaction is complete, unscrew the flange and open the reactor lid. Take out the whole product and divide it into three parts: upper, middle and lower. Crush each part into small pieces. Take appropriate amounts of product samples from the crushed upper, middle and lower parts to test their intrinsic viscosity, as shown in Table 9 below. The monomer residue of each part is measured by gas chromatography, and the mass percentage of monomer residue is shown in Table 9 below, which is recorded as monomer residue (before extraction). Then, place the product samples from the upper, middle and lower parts into supercritical carbon dioxide for extraction. The monomer residue after extraction is also measured by gas chromatography, and the values ​​are also shown in Table 9, which is recorded as monomer residue (after extraction).

[0170] Table 9

[0171] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.10 4.11 4.11 Monomer residue (before extraction) 2.82wt% 2.83wt% 2.81wt% Monomer residue (after extraction) 0.40wt% 0.41wt% 0.40wt%

[0172] Comparing Table 1 and Table 9, it can be found that the product still has high intrinsic viscosity, good uniformity and low monomer residue after the capacity expansion.

[0173] Example 7

[0174] The preparation process is basically the same as in Example 6, except that L-lactide in step (2) is replaced with the same mass of glycolide, and the reaction time in step (4) is replaced with 7 days.

[0175] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the sample in this example were obtained and are listed in Table 10 below.

[0176] Table 10

[0177] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.20 4.20 4.21 Monomer residue (before extraction) 2.91wt% 2.94wt% 2.85wt% Monomer residue (after extraction) 0.45wt% 0.47wt% 0.44wt%

[0178] As shown in Table 10, the present invention can prepare large quantities of polyglycolic acid with high intrinsic viscosity and good uniformity.

[0179] Example 8

[0180] The preparation process is basically the same as in Example 6, except that L-lactide in step (2) is replaced with the same mass of ε-caprolactone, and the reactor temperature in step (4) is replaced with 120°C and the reaction time is replaced with 4 days.

[0181] Using the same test method as in Example 1, the intrinsic viscosity, monomer residue before extraction, and monomer residue after extraction of the upper, middle, and lower parts of the sample in this example were obtained and are listed in Table 11 below.

[0182] Table 11

[0183] upper part Central lower part Intrinsic viscosity (IV) / dL / g 4.85 4.85 4.85 Monomer residue (before extraction) 2.13wt% 2.11wt% 2.12wt% Monomer residue (after extraction) 0.40wt% 0.41wt% 0.40wt%

[0184] As shown in Table 11, the present invention can prepare large quantities of poly(ε-caprolactone) with high intrinsic viscosity and good uniformity.

[0185] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. The specific examples used above to illustrate the present invention are only for the purpose of helping to understand the present invention and are not intended to limit the present invention. Those skilled in the art to which this invention pertains can make several simple deductions, modifications, substitutions, or combinations based on the concept of the present invention. These deductions, modifications, substitutions, or combinations also fall within the scope of the claims of the present invention.

Claims

1. A method for preparing a highly uniform medical-grade absorbable polyester, characterized in that, The system used includes a closed-loop agitator, an additive tank, a three-way valve, and a closed-loop reactor. The three-way valve is connected to the closed-type agitator via a melt metering pump. The three-way valve is connected to the auxiliary agent container via a micro-injection pump; The three-way valve is connected to the closed-loop reactor via a static mixer; The three-way valve is designed in a funnel shape on the side connected to the micro-injection pump, including a funnel neck and a funnel opening. The side and bottom of the funnel neck are provided with uniform small holes. The specific preparation method is as follows: S1: Open all valves to replace the entire system with an inert gas atmosphere and continuously purge with inert gas; S2: Under an inert gas atmosphere, the reaction monomer and inorganic sodium salt are added to the closed stirrer and heated to melt. The resulting melt is then fed into a melt metering pump and then into a three-way valve. S3: The catalyst, initiator and organic solvent are mixed evenly to obtain an auxiliary agent solution. The auxiliary agent solution is injected into the auxiliary agent tank and then introduced into a three-way valve through a micro-injection pump. S4: In the three-way valve, the melt and the additive solution are fully mixed at an appropriate flow rate and then introduced into the static mixer. After further homogenization, it is introduced into the closed autoclave reactor. After all the materials have entered, the reactor is heated to carry out the polymerization reaction to obtain a highly uniform medical-grade absorbable polyester. The speed of the melt metering pump is 0.5~3.0 L / min, and the speed of the micro-injection pump is 1~10‰ of the speed of the melt metering pump.

2. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that: The diameter of the funnel neck is selected from 0.25 to 1.5 mm, and the maximum diameter of the funnel opening is 3 to 6 times the diameter of the funnel neck; The diameter of the small holes on the side and bottom of the funnel neck is 5-40% of the diameter of the funnel neck; The height of the bottom surface of the funnel neck from the bottom of the three-way valve is 25-45% of the inner diameter of the three-way valve.

3. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that: The closed-loop reactor can be one unit or N units connected in parallel, where N≤10; The volume of a single closed-loop reactor is 1~10L.

4. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that, In step S2: The reaction monomers are selected from one or more of the following: L-lactide, D-lactide, racemic lactide, glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and lactam. The inorganic sodium salt is selected from sodium chloride and / or sodium carbonate; The mass of the inorganic sodium salt is 0.01 to 5.00 wt% of the mass of the reactant monomer.

5. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that, In step S2: After adding the reactant monomer and inorganic sodium salt to a closed stirrer, the vacuum was first drawn to a level of -0.1 MPa, and then an inert gas was introduced to reach atmospheric pressure before heating and melting. The heating temperature for melting depends on the melting point of the reactant monomer; it is sufficient to heat the reactant monomer until it forms a melt. The stirring speed in the closed-type agitator is 50~500 rpm.

6. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that, In step S3: The catalyst is selected from one or more of tin compounds, zinc compounds, antimony compounds, and basic organic catalysts; The initiator is selected from polyols and / or polyacids; Based on the mass of the reactant monomer, the amount of catalyst added is 10~500ppm and the amount of initiator added is 30~5000ppm; The organic solvent is selected from one or more of toluene, xylene, dimethyl sulfoxide, dichloromethane, and trichloromethane; The concentration of the auxiliary agent in the solution is 0.005~0.25 g / mL.

7. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that, In step S3: The auxiliary agent container is under a slightly positive pressure, with the pressure value selected from 0.1~1.0 MPa.

8. The method for preparing highly uniform medical-grade absorbable polyester according to claim 1, characterized in that, In step S4: The closed-loop reactor is equipped with a magnetic stirrer with a stirring speed of 100~700 rpm; The temperature and time of the polymerization reaction are adjusted according to the type of monomer used.

9. A highly uniform medical-grade absorbable polyester prepared according to any one of claims 1 to 8.

Images