CN113717362B - Suspension polymerization preparation method of injectable lactide-glycolide copolymer - Google Patents
Suspension polymerization preparation method of injectable lactide-glycolide copolymer Download PDFInfo
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
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- C—CHEMISTRY; METALLURGY
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
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Abstract
The invention discloses a suspension polymerization preparation method of injectable lactide-glycolide copolymer, which adopts polyethylene glycol dimethyl ether and/or polypropylene glycol dimethyl ether as suspending agent, and mixes the suspending agent with raw materials of glycolide, lactide, catalyst and initiator to carry out ring-opening polymerization reaction to prepare the lactide-glycolide copolymer. The preparation method can effectively solve the problems of difficult heat transfer, difficult post-treatment and the like in the existing bulk melt polymerization method, and the obtained polymer has high purity, simple refining process and no need of secondary molding.
Description
Technical Field
The invention belongs to the field of preparation of biomedical high polymer materials, and particularly relates to a preparation method of a lactide-glycolide copolymer for injection.
Background
The lactide-glycolide copolymer is an important biomedical polymer material, has the advantages of two polyester materials of polylactic acid and polyglycolic acid, has various performances of good biocompatibility, biodegradability, degradation rate adjustability, easy processing and the like, and is widely applied to the biomedical fields of surgical sutures, fracture internal fixation materials, tissue repair materials, drug sustained and controlled release systems and the like.
At present, the synthesis methods of lactide glycolide polymers mainly comprise a direct method and an indirect method. The direct method is to prepare the copolymer by taking lactic acid and glycolic acid as raw materials and adopting a solution polymerization or melt polymerization mode. Although the method has simple process, the reaction conditions are relatively harsh, and the molecular weight of the polymer synthesized in the early stage is relatively low. The indirect method is that lactic acid and glycollic acid are first prepared into intermediate glycolide and lactide separately, and the glycolide and lactide are then melt polymerized to prepare copolymer. The method can obtain the copolymer with high molecular weight, but the reaction heat in the reaction process is difficult to eliminate, the reaction process is difficult to control, the post-treatment is difficult, and the reaction is difficult to amplify.
To overcome the above two drawbacks, the suspension polymerization method has been studied to prepare the poly (lactide-co-glycolide). British patents (patent nos. BP235335 and 932382) report on a series of suspension polymerizations of glycolide and lactide in a non-aqueous system. In the series of experiments, various types of gasoline are used, and the stabilizer used in the system is silicone oil, so that the low-molecular-weight copolymer is synthesized. Chinese patent CN101343354B selects alkane with boiling point higher than 90 ℃ as suspending agent and silicon oil as stabilizing agent to synthesize a series of copolymers. The setron and the like use methyl silicone oil as a dispersion medium to synthesize polyglycolide with relatively high molecular weight. However, gasoline and high boiling point alkane belong to flammable liquids, and the container has explosion danger when heated, so that the safety is poor; and the silicone oil used as a stabilizer and a dispersion medium is difficult to handle in the refining process. Therefore, the selection of a suspending agent with high safety and easy handling is the key to the realization of the suspension polymerization industrial production of the lactide-glycolide copolymer.
Disclosure of Invention
The invention aims to provide a suspension polymerization preparation method of a lactide-glycolide copolymer for injection, which aims to solve the problems of poor safety, difficult post-treatment and the like of the existing suspending agent.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for preparing the lactide-glycolide copolymer for injection by suspension polymerization features that the polyethylene glycol dimethyl ether and/or polypropylene glycol dimethyl ether as suspending agent are mixed with glycolide, lactide, catalyst and trigger for ring-opening polymerization reaction.
As a further improvement of the present invention, the method comprises the steps of:
adding raw materials of glycolide, lactide, polyethylene glycol dimethyl ether and/or polypropylene glycol dimethyl ether suspending agent into a reaction container, uniformly stirring, vacuumizing, and repeatedly pumping nitrogen to regulate the pressure to normal pressure;
adding a catalyst and a fatty alcohol initiator into a reaction vessel under the protection of nitrogen, stirring and heating;
after glycolide and lactide are completely melted, adjusting the stirring rate, and continuously heating for ring-opening polymerization reaction;
after the reaction is stopped, stirring is continuously carried out to room temperature, and the product is obtained by filtration.
As a further improvement of the invention, the reaction is carried out under the conditions of no water and no oxygen, mechanical stirring and inert gas protection.
As a further improvement of the invention, the molecular weight of the suspending agent is 200 to 1000.
As a further improvement of the invention, the ratio of the dosage of the suspending agent to the total mass of the raw materials of glycolide and lactide is 2-1, and preferably 3.
As a further improvement of the invention, the catalyst is stannous octoate, and the dosage of the catalyst is 0.02-0.1%, preferably 0.03-0.05% of the total mass of the raw materials glycolide and lactide.
As a further improvement of the invention, lauryl alcohol is selected as the initiator.
As a further improvement of the invention, the ring-opening polymerization reaction is carried out under the protection of anhydrous oxygen-free and inert gas.
As a further improvement of the invention, the temperature is raised to 120 ℃ by stirring and maintained until the glycolide and the lactide are completely melted and uniformly dispersed; then the temperature is raised to 140-180 ℃ to continue the polymerization reaction.
As a further improvement of the invention, the ring-opening polymerization reaction time is 6 to 24 hours, preferably 10 to 16 hours.
As a further improvement of the invention, the ring-opening polymerization reaction is firstly stirred and heated at 100rpm, and after the glycolide and the lactide are completely melted, the stirring speed is adjusted to 300-500 rpm.
Further, a granular product is generated by reaction, and the lactide-glycolide copolymer is obtained after refining treatment.
The invention has the following beneficial effects:
(1) The lactide-glycolide copolymer prepared by the suspension polymerization method can effectively solve the problems that the reaction heat is difficult to eliminate, the reaction process is difficult to control, the post-treatment is difficult and the like during the bulk melt polymerization;
(2) Polyethylene glycol dimethyl ether and/or polypropylene glycol dimethyl ether are/is used as a suspending agent, so that the defects of poor safety, difficult post-treatment and the like of the suspending agent in the existing suspension polymerization technology are overcome; the copolymer is washed by organic solvent such as alcohol, and the copolymer with high purity can be obtained, and the polymer is granular and does not need secondary forming.
(3) During the reaction, a nitrogen replacement mode after vacuumizing is adopted, air and moisture in the system are removed as much as possible, so that the subsequent polymerization reaction is not influenced, and the step is carried out under normal-temperature stirring; after the nitrogen replacement is finished, adopting a two-stage heating program, firstly adding a catalyst and an initiator under the protection of nitrogen, heating to 120 ℃ while stirring, and maintaining for a period of time until the lactide monomer in the system is completely melted and uniformly dispersed; then heating to 140-180 ℃ to continue the polymerization reaction. The molecular weight and the distribution of the polymer can be effectively ensured, so that the polymer meets the requirement of injection, and the molecular weight distribution coefficient of the final product is between 1.0 and 2.0;
(4) The invention has the advantages of simple required equipment and process, strong operability and repeatability, economy and safety of the selected suspending agent and contribution to the realization of industrial production of the lactide-glycolide copolymer.
Detailed Description
Example 1
30g of lactide, 8.06g of glycolide and 114g of polyethylene glycol dimethyl ether (molecular weight is 1000) are weighed and added into a 250mL three-neck flask, the mixture is stirred to 100rpm, the mixture is vacuumized for 15min, then nitrogen is introduced to the normal pressure, and the nitrogen is repeatedly pumped and changed for 3 times. Under the protection of nitrogen, 0.0114g of stannous octoate and 0.7g of lauryl alcohol are added into a three-neck flask, and the temperature is raised to 120 ℃; after the glycolide and the lactide are completely melted, the rotating speed is adjusted to 300rpm, and the temperature is continuously increased to 140 ℃ for reaction for 12 hours. Stopping reaction, continuously stirring to room temperature in cooling, and filtering to obtain the lactide-glycolide copolymer particles. Washing with ethanol for three times, and drying to obtain the lactide-glycolide copolymer. Chloroform is used as a solvent, and the intrinsic viscosity of the copolymer is measured by a Ubbelohde viscometer at 25 ℃ and is 20mL/g; the molecular weight of the copolymer was 11534 and the molecular weight distribution coefficient was 1.2 by GPC using tetrahydrofuran as a solvent.
Example 2
30g of lactide, 8.06g of glycolide and 190g of polyethylene glycol dimethyl ether (molecular weight is 600) are weighed and added into a 500mL three-neck flask, the stirring is started to 100rpm, the vacuum is pumped for 15min, then nitrogen is introduced to the normal pressure, and the nitrogen is pumped and exchanged for 3 times repeatedly. Under the protection of nitrogen, 0.0114g of stannous octoate and 0.7g of lauryl alcohol are added into a three-neck flask, and the temperature is raised to 120 ℃; after the glycolide and the lactide are completely melted, the rotating speed is adjusted to 300rpm, and the temperature is continuously increased to 140 ℃ for reaction for 12 hours. Stopping reaction, continuously stirring to room temperature in cooling, and filtering to obtain the lactide-glycolide copolymer particles. Washing with ethanol for three times, and drying to obtain the lactide-glycolide copolymer. Measuring the intrinsic viscosity of the copolymer by using a Ubbelohde viscometer at 25 ℃ by using trichloromethane as a solvent, wherein the intrinsic viscosity of the copolymer is 19mL/g; the molecular weight of the copolymer measured by GPC was 10178 using tetrahydrofuran as a solvent, and the molecular weight distribution coefficient was 1.2.
Example 3
30g of lactide, 8.06g of glycolide and 114g of polypropylene glycol dimethyl ether (molecular weight is 1000) are weighed and added into a 250mL three-neck flask, the mixture is stirred to 100rpm, the mixture is vacuumized for 15min, then nitrogen is introduced to the normal pressure, and the nitrogen is repeatedly pumped and changed for 3 times. Under the protection of nitrogen, 0.0114g of stannous octoate and 0.7g of lauryl alcohol are added into a three-neck flask, and the temperature is raised to 120 ℃; after the glycolide and the lactide are completely melted, the rotating speed is adjusted to 300rpm, and the temperature is continuously increased to 160 ℃ for reaction for 10 hours. Stopping reaction, continuously stirring to room temperature in cooling, and filtering to obtain the lactide-glycolide copolymer particles. Washing with ethanol for three times, and drying to obtain the lactide-glycolide copolymer. Chloroform is used as a solvent, and the intrinsic viscosity of the copolymer is measured by a Ubbelohde viscometer at 25 ℃ and is 18mL/g; the molecular weight of the copolymer was 10267 and the molecular weight distribution coefficient was 1.3 by GPC using tetrahydrofuran as a solvent.
Example 4
24.8g of lactide, 20g of glycolide and 269g of polypropylene glycol dimethyl ether (molecular weight 600) are weighed into a 500mL three-neck flask, stirred to 100rpm, vacuumized for 15min, then nitrogen is introduced to normal pressure, and nitrogen is repeatedly pumped and changed for 3 times. Adding 0.0224g of stannous octoate and 0.40g of lauryl alcohol into a three-neck flask under the protection of nitrogen, and heating to 120 ℃; after the glycolide and the lactide are completely melted, the rotating speed is adjusted to 300rpm, and the temperature is continuously increased to 180 ℃ for reaction for 24 hours. Stopping reaction, continuously stirring to room temperature in cooling, and filtering to obtain the lactide-glycolide copolymer particles. Washing with ethanol for three times, and drying to obtain the lactide-glycolide copolymer. Chloroform is used as a solvent, and the intrinsic viscosity of the copolymer is measured to be 32mL/g by a Ubbelohde viscometer at 25 ℃; the molecular weight of the copolymer was 22132 and the molecular weight distribution coefficient was 1.8 by GPC using tetrahydrofuran as a solvent.
Example 5
30g of lactide, 8.06g of glycolide and 76g of polyethylene glycol dimethyl ether (molecular weight 200) are weighed and added into a 250mL three-neck flask, the stirring is started to 100rpm, the vacuum pumping is carried out for 15min, then nitrogen is introduced to the normal pressure, and the nitrogen is repeatedly pumped and changed for 3 times. Under the protection of nitrogen, 0.0114g of stannous octoate and 0.14g of lauryl alcohol are added into a three-neck flask, and the temperature is raised to 120 ℃; after the glycolide and the lactide are completely melted, the rotating speed is adjusted to 300rpm, and the temperature is continuously increased to 160 ℃ for reaction for 16h. The reaction was stopped, stirring was continued to room temperature while cooling, and the lactide-glycolide copolymer particles were obtained by filtration with a small amount of particle aggregates. Washing with ethanol for three times, and drying to obtain the lactide-glycolide copolymer. Chloroform is used as a solvent, and the intrinsic viscosity of the copolymer is measured to be 45mL/g by a Ubbelohde viscometer at 25 ℃; the molecular weight of the copolymer measured by GPC with tetrahydrofuran as solvent was 42132, and the molecular weight distribution coefficient was 2.0.
Example 6
30g of lactide, 8.06g of glycolide, 190g of polyethylene glycol dimethyl ether (molecular weight 400) and 190g of polypropylene glycol dimethyl ether (molecular weight 400) are weighed and added into a 500mL three-neck flask, the mixture is stirred to 100rpm, the mixture is vacuumized for 15min, then nitrogen is introduced to the normal pressure, and the nitrogen is repeatedly pumped and replaced for 3 times. Under the protection of nitrogen, 0.0114g of stannous octoate and 0.7g of lauryl alcohol are added into a three-neck flask, and the temperature is raised to 120 ℃; after the glycolide and the lactide are completely melted, the rotating speed is adjusted to 300rpm, and the temperature is continuously increased to 160 ℃ for reaction for 24 hours. Stopping reaction, continuously stirring to room temperature in cooling, and filtering to obtain the lactide-glycolide copolymer particles. Washing with ethanol for three times, and drying to obtain the lactide-glycolide copolymer. Measuring the intrinsic viscosity of the copolymer by using a Ubbelohde viscometer at 25 ℃ by using trichloromethane as a solvent, wherein the intrinsic viscosity of the copolymer is 15mL/g; the molecular weight of the copolymer was 7445 and the molecular weight distribution coefficient was 1.6 by GPC using tetrahydrofuran as a solvent.
Claims (8)
1. A suspension polymerization preparation method of injectable lactide-glycolide copolymer is characterized by comprising the following steps:
adding glycolide, lactide and polyethylene glycol dimethyl ether as raw materials into a reaction container, uniformly stirring, vacuumizing, and repeatedly pumping nitrogen to regulate the pressure to normal pressure; the mass ratio of the suspending agent to the total mass of the glycolide and the lactide serving as reaction raw materials is 2 to 1-10;
adding a catalyst and a fatty alcohol initiator into a reaction vessel under the protection of nitrogen, stirring and heating;
after glycolide and lactide are completely melted, adjusting the stirring rate, and continuously heating for ring-opening polymerization reaction;
after the reaction is stopped, continuously stirring to room temperature, filtering to obtain granular products, and refining to obtain the lactide-glycolide copolymer.
2. The method of claim 1, wherein the suspending agent has a molecular weight of 200 to 1000.
3. The preparation method according to claim 1, wherein the ratio of the suspending agent to the total mass of the raw materials, namely glycolide and lactide, is 3 to 1.
4. The preparation method of claim 1, wherein the catalyst is stannous octoate, and the amount of the catalyst is 0.02-0.1% of the total mass of the raw materials glycolide and lactide.
5. The method according to claim 1, wherein the initiator is lauryl alcohol.
6. The preparation method of claim 1, wherein the temperature is raised to 120 ℃ by stirring and maintained until the glycolide and the lactide are completely melted and uniformly dispersed; then heating to 140-180 ℃ to continue the polymerization reaction.
7. The process according to claim 1, wherein the ring-opening polymerization reaction time is 6 to 24h.
8. The preparation method according to claim 1, wherein the ring-opening polymerization reaction is carried out by stirring at 100rpm and heating, and after the glycolide and the lactide are completely melted, the stirring rate is adjusted to 300 to 500rpm.
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| WO2017005483A1 (en) * | 2015-07-09 | 2017-01-12 | Evonik Röhm Gmbh | Process for preparing poly(glycolide-co-lactide) copolymer microparticles |
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