CN111019107A

CN111019107A - Preparation method of multi-branched poly (glycolide-lactide)

Info

Publication number: CN111019107A
Application number: CN201911376471.1A
Authority: CN
Inventors: 袁文博; 苏红清; 李建; 赵春华; 秦昌
Original assignee: Shandong Guyuchun Biotechnology Technology Co ltd
Current assignee: Shandong Guyuchun Biotechnology Technology Co ltd
Priority date: 2019-12-27
Filing date: 2019-12-27
Publication date: 2020-04-17

Abstract

The invention belongs to the technical field of organic polymer synthesis, and particularly relates to a preparation method of multi-branched-chain poly (glycolide-lactide). By adopting the invention, high-temperature reaction is avoided, energy consumption is saved, and the method is safer; the use of heavy metals is avoided; the post-treatment operation is simple, and qualified products can be obtained.

Description

Preparation method of multi-branched poly (glycolide-lactide)

Technical Field

The invention belongs to the technical field of organic polymer synthesis, and particularly relates to a preparation method of multi-branched poly (glycolide-lactide).

Background

Compared with single linear macromolecule, the multi-branched-chain macromolecule polymer can improve the physical, chemical and biological properties to a certain extent. The research shows that the multi-branched polymer has better biocompatibility in human body, larger drug loading capacity, more excellent biodegradability and better processability compared with the linear polymer. The multi-branched polymer has potential application prospect due to novel structure and unique performance.

Among various polymers, poly (lactic-co-glycolic acid) (PLGA) has good biodegradability and biocompatibility, and is widely applied to biomedical tissue engineering, such as bioabsorption suture materials, tissue engineering materials, drug controlled release systems and the like. PLGA has been approved by the FDA as one of the commonly used drug carriers due to its low toxicity. However, the straight-chain PLGA still has certain disadvantages when used as a drug carrier, is difficult to introduce a large number of functional groups, and is easily recognized and phagocytized by the reticuloendothelial system in vivo, thereby preventing the drug from reaching the target site and reducing the bioavailability of the drug. Therefore, the development of novel multi-branched PLGA has wide application prospect.

The traditional preparation method of the PLGA with the branched chains is a ring-opening polymerization method, glycolide and lactide are used as raw materials for melt polymerization, polyhydroxy compounds are used as initiators for regulating the molecular weight, and the multi-branched PLGA is synthesized at high temperature under the catalysis of heavy metal catalysts. In the method, the reaction temperature is generally above 150 ℃, most of catalysts are heavy metal catalysts, and the products are easily carbonized due to local overheating under the high-temperature condition; heavy metal catalysts accumulate in the human body to a certain extent, and cause chronic poisoning.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a preparation method of multi-branched poly (glycolide-co-lactide). By adopting the invention, high-temperature reaction is avoided, energy consumption is saved, and the method is safer; the use of heavy metals is avoided; the post-treatment operation is simple, and qualified products can be obtained.

The preparation method of the multi-branched-chain poly (glycolide) provided by the invention adopts lactide monomers and glycolide monomers as raw materials, adopts Lewis acid as a catalyst, and carries out reaction at 20-30 ℃, and after the reaction is finished, the multi-branched-chain poly (glycolide) is dissolved, precipitated and dried to obtain the multi-branched-chain poly (glycolide).

The lactide monomer and the glycolide monomer are dissolved in a solvent to prepare a suspension, and the solvent is selected from dichloromethane or trichloromethane or toluene or tetrahydrofuran; after the reaction solvent is adopted, the lactide and the glycolide can be dispersed and mixed in the solvent, and the reaction temperature is reduced to a certain extent. Lactide monomer: the glycolide monomer accounts for 50: 50-85: 15.

The mass-volume ratio of the total mass of the monomers to the volume of the solvent is 1:1-1:5, the monomers comprise lactide monomers and glycolide monomers, and the unit of the mass-volume ratio is kg/L. The monomer having an excessively small proportion is not uniformly dispersed, and an excessively large proportion increases the volume of the reaction system and prolongs the reaction time.

The Lewis acid is selected from trifluoromethanesulfonic acid or trifluoroethanesulfonic acid or methanesulfonic acid or a mixture thereof, and H is extremely easy to ionize by the electron-withdrawing induction effect of the catalyst.

The dosage of the catalyst is 0.05-0.5 times of the total molar weight of the lactide monomer and the glycolide monomer, the catalyst cannot perform catalytic reaction when the proportion is too small, side reaction can be generated when the proportion is too large, and the post-treatment difficulty is increased.

The reaction time is generally 6 to 8 hours in the present invention. After the reaction is finished, jelly containing crude poly (glycolide-lactide) and unreacted monomers is obtained. Adding a benign solvent into the jelly to dissolve the jelly, then adding a poor solvent to precipitate until no precipitate is generated, separating out supernatant, adding the benign solvent and the poor solvent to precipitate, and repeatedly dissolving and precipitating for three times. The benign solvent is selected from dichloromethane or chloroform or tetrahydrofuran or toluene or xylene, and the poor solvent is selected from methanol or ethanol or n-hexane or n-heptane or diethyl ether. The mass-to-volume ratio of the total monomer mass to the benign solvent is 1-5 kg/L. The volume ratio of the benign solvent to the poor solvent is 1: 0.8-1: 2.

In conclusion, the invention prepares reactants lactide and glycolide into a suspension state by using a solvent, adopts an organic catalyst to catalyze the reaction at normal temperature to obtain a colloidal product, and then refines and dries the product by recrystallization of the organic solvent to finally obtain the target product. Compared with the prior art, the method avoids high-temperature reaction, saves energy consumption and is safer; the use of heavy metals is avoided; the post-treatment operation is simple.

Drawings

FIG. 1 is a chromatogram of the product of example 1;

FIG. 2 is a chromatogram of the product of example 2;

FIG. 3 is a chromatogram of the product of example 3;

FIG. 4 is a chromatogram of the product of example 4.

Detailed Description

Example 1

Weighing 120g of lactide monomer (LA) and 80g of glycolide monomer (GA), pouring into a three-neck flask, adding 200mL of dichloromethane, stirring, weighing 0.05 equivalent of trifluoromethanesulfonic acid and 3.0g of glycerol, adding into the three-neck flask, replacing 3 times with nitrogen, reacting at 20 ℃ for 6-8 hours to obtain a jelly, dissolving with dichloromethane, precipitating with ethanol for three times, wherein the amount of dichloromethane is 200mL each time, and the volume of ethanol is 200mL, vacuum drying is carried out until the weight is constant to obtain a finished product, the yield is 87.65%, Mw38538, Mn20640 and the viscosity is 56.79.

Example 2

Weighing 120g of lactide monomer (LA) and 80g of glycolide monomer (GA), pouring into a three-neck flask, adding 300mL of dichloromethane, stirring, weighing 0.10 equivalent of trifluoroethanesulfonic acid and 3.5g of pentaerythritol, adding into the three-neck flask, replacing with nitrogen for 3 times, reacting at 30 ℃ for 8-10 hours to obtain a jelly, dissolving with chloroform and precipitating with ethanol for three times, wherein the dosage of chloroform is 400mL each time, and vacuum drying 480mL of ethanol to constant weight to obtain the finished product, wherein the yield is 83.71%, Mw52091, Mn34697, and the viscosity is 60.16

Example 3

Weighing 140g of lactide monomer (LA) and 60g of glycolide monomer (GA), pouring into a three-neck flask, adding 800mL of chloroform, stirring, weighing 0.05 equivalent of trifluoromethanesulfonic acid and 4g of glucose, adding into the three-neck flask, replacing with nitrogen for 3 times, reacting at 25 ℃ for 8-10 hours to obtain a jelly, adding tetrahydrofuran for dissolution, precipitating with methanol for 3 times, wherein the amount of tetrahydrofuran is 600mL each time, and the amount of methanol is 480mL, and vacuum drying to constant weight to obtain a finished product, wherein the yield is 86.35%, Mw52209, Mn37745, and viscosity 70.10

Example 4

Weighing 20g of lactide monomer (LA) and 5g of glycolide monomer (GA), pouring into a three-neck flask, adding 120mL of tetrahydrofuran, stirring, weighing 0.10 equivalent of methanesulfonic acid and 0.6g of pentaerythritol, adding into the three-neck flask, performing nitrogen replacement for 3 times, reacting at 30 ℃ for 8-10 hours to obtain a jelly, dissolving with toluene, precipitating with n-hexane for three times, wherein the amount of toluene is 120mL each time, and drying with 120mL of n-hexane in vacuum to constant weight to obtain a finished product, wherein the yield is 81.23%, Mw21108, Mn14024 and viscosity is 26.7.

Claims

1. A process for preparing multi-branched-chain poly (glycolide-lactide) features that the lactide monomer and glycolide monomer are used as raw materials, and the reaction is carried out at 20-30 deg.C in the presence of alkyl sulfonic acid as catalyst, and the multi-branched-chain poly (glycolide-lactide) is prepared through dissolving, depositing and drying.

2. The method for preparing multi-branched poly (glycolide-lactide) according to claim 1, wherein the lactide monomer and the glycolide monomer are dissolved in a solvent to form a suspension.

3. The method for preparing multi-branched poly (glycolide-lactide) according to claim 1, wherein the ratio of lactide monomer(s): the glycolide monomer accounts for 50: 50-85: 15.

4. The method for preparing multi-branched poly (glycolide-lactide) according to claim 2, wherein the solvent is selected from dichloromethane or trichloromethane or toluene or tetrahydrofuran, the mass-to-volume ratio of the total mass of the monomers to the volume of the solvent is 1:1-1:5, the monomers comprise lactide monomer and glycolide monomer, and the unit of the mass-to-volume ratio is kg/L.

5. The process for preparing poly-branched poly (glycolide-lactide), according to claim 2, wherein the Lewis acid is selected from the group consisting of trifluoromethanesulfonic acid, trifluoroethanesulfonic acid, methanesulfonic acid and mixtures thereof.

6. The method of claim 2, wherein the amount of the catalyst is 0.05 to 0.5 times the total molar amount of the lactide monomer and the glycolide monomer.

7. The process according to claim 2, wherein the dissolution is carried out in a benign solvent, and the mass-to-volume ratio of the total monomer mass to the benign solvent is 1 to 5 kg/L.

8. The process according to claim 7, wherein the benign solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene and xylene.

9. The preparation method of the multi-branched poly (glycolide-lactide) according to claim 2, wherein the poor solvent is adopted for precipitation, and the volume ratio of the benign solvent to the poor solvent is 1: 0.8-1: 2.

10. The method for preparing multi-branched poly (glycolide-lactide) according to claim 9, wherein the poor solvent is selected from methanol, ethanol, n-hexane, n-heptane or diethyl ether.