阅读说明：本技术 一种制备聚乳酸的方法 (Method for preparing polylactic acid ) 是由 王林鹏 安宁 万龙岩 单连民 董瑞琦 于 2021-08-03 设计创作，主要内容包括：本发明提供一种制备聚乳酸的方法,其包括以下步骤：(a)在分子量调节剂的存在下,使乳酸预聚合；(b)在催化剂的存在下,使预聚合产物进行缩聚以得到所述聚乳酸；所述催化剂选自质子酸化合物。本发明方法以乳酸为原料,采用非金属类催化剂,能够绿色、高效地提供纯度高、分子量规整、低金属残留甚至无金属残留的医药级聚乳酸材料。(The invention provides a method for preparing polylactic acid, which comprises the following steps: (a) prepolymerizing lactic acid in the presence of a molecular weight regulator; (b) polycondensing the prepolymerized product in the presence of a catalyst to obtain the polylactic acid; the catalyst is selected from protonic acid compounds. The method of the invention uses lactic acid as a raw material and adopts a non-metal catalyst, and can provide a pharmaceutical grade polylactic acid material with high purity, regular molecular weight, low metal residue and even no metal residue in a green and high-efficiency manner.)

1. A method of preparing polylactic acid, comprising the steps of:

(a) prepolymerizing lactic acid in the presence of a molecular weight regulator;

(b) polycondensing the prepolymerized product in the presence of a catalyst to obtain the polylactic acid;

the catalyst is selected from protonic acid compounds.

2. The method of claim 1, further comprising the step of dehydrating lactic acid prior to step (a);

preferably, the dehydration step is such that the lactic acid has a water content of < 2 wt.%;

preferably, the dehydration step is performed at a temperature of 110 ℃ to 130 ℃ and a vacuum degree of-0.08 MPa to-0.1 MPa.

3. The method according to claim 1 or 2, wherein the protonic acid compound is selected from at least one of sulfuric acid, sodium dodecylbenzenesulfonate, p-toluenesulfonic acid, acetic acid;

preferably, the protonic acid compound is sulfuric acid.

4. A method according to any of claims 1 to 3, characterized in that the amount of catalyst is 0.01-0.15 wt.%, preferably 0.01-0.1 wt.% of the prepolymerised product.

5. The process according to any one of claims 1 to 4, characterized in that the prepolymerization is carried out at a temperature of 140 ℃ to 150 ℃ and a vacuum of-0.08 MPa to-0.1 MPa;

preferably, the prepolymerization is carried out for 1 to 3 hours.

6. The method according to any one of claims 1 to 5, wherein the molecular weight regulator is selected from phosphoric acid or lactic acid;

preferably, the amount of the molecular weight regulator is 0.01 wt.% to 0.1 wt.% of the raw material lactic acid.

7. Process according to any one of claims 1 to 6, characterized in that the polycondensation is carried out at a temperature of 150 ℃ to 170 ℃ and a vacuum of-0.08 MPa to-0.12 MPa;

preferably, the polycondensation is carried out at a temperature of 160 ℃ to 170 ℃ and a vacuum degree of-0.1 MPa;

preferably, the polycondensation is carried out for 3 to 6 hours.

8. Process according to any one of claims 1 to 7, characterized in that the polycondensation is carried out in the presence of a protective gas.

9. The method according to any one of claims 1 to 8, characterized in that the method further comprises a step of purifying the polylactic acid after step (b);

preferably, the purification step comprises dissolving the polycondensation product with a good solvent and then precipitating out with a poor solvent;

preferably, the polylactic acid is vacuum dried at 25 to 50 ℃.

10. The method according to claim 9, wherein the good solvent is selected from at least one of acetone and chloroform; the poor solvent is selected from at least one of water, ethanol and methanol;

preferably, the purification step comprises dissolving the polylactic acid with acetone, and then precipitating with water and ethanol.

Technical Field

The invention belongs to the field of materials. In particular, the present invention relates to a method for preparing polylactic acid.

Background

Polylactic acid (PLA) is a biodegradable, biocompatible polymer polyester that is well tolerated in vivo. PLA has three spatial configurations: PDLA (dextrorotation), PLLA (levorotation), PDLLA (dextrorotation). Among them, PDLA and PLLA are semi-crystalline materials, have high strength and slow degradation rate in vivo, and after being reprocessed, are mainly widely used as bio-absorption materials in the medical field. PDLLA is a non-crystalline material, and the medicament is easy to be uniformly distributed in the matrix of the PDLLA, is combined with a preparation process and is mainly applied to a medicament controlled release system. By further adjusting the average molecular weight, the crystallinity and the ratio of the mixed spinning of the PDLLA polymer, the degradation rate of the polymer can be regulated, thereby indirectly realizing the control of the release of the medicament in vivo.

No matter the medical or medicinal use, higher requirements are put forward on the PLA material (the size of molecular weight, the molecular weight distribution, the crystal form, the mixed rotation proportion, the purity, the sterility and the like). Not only biological safety is required, but also other indexes must meet medical or medicinal related requirements, and stability and reliability are required. Therefore, the synthesis process of the medicinal PLA is very important.

At present, the PLA synthesis process mainly includes two methods, Direct Polymerization (DP) and lactide ring-opening polymerization (ROP). Chinese patent application publication CN1631932A discloses a method for producing biodegradable plastic, which uses lactic acid as raw material, and polycondenses the lactic acid under high temperature and reduced pressure in the presence of metal catalyst to obtain biodegradable plastic with polylactic acid as main component. Chinese patent application publication CN1613889A discloses a method for preparing high molecular weight polylactic acid on a twin-screw extruder, which comprises pre-polymerizing lactic acid monomer, and then chain extending on the twin-screw extruder to obtain high molecular weight polylactic acid, wherein a metal catalyst is also used in the pre-polymerization process. PLA synthesized by such a method is not suitable as a matrix for medical and food-type materials due to the use and residue of metal catalysts. Although stannous octoate is approved by the FDA as a catalyst for PLA synthesis for medical use, it is increasingly under the list of bans by some developed countries. In addition, the existing methods have the problems of more byproducts and difficult product separation, especially the viscosity is increased continuously in the later stage of polycondensation, and stirring and water removal are difficult, so that the synthesis of polymers with higher molecular weight is difficult. The synthesis by adopting a double-screw extruder or a special reaction kettle needs more complex supporting facilities.

The ring-opening polymerization using lactide as a raw material is another way to obtain polylactic acid. Chinese patent application publication CN101429276A discloses a method for synthesizing molecular weight controllable polylactic acid without metal residue. Chinese patent application publication CN103923305A discloses an environment-friendly catalyst-improved prepared polylactic acid resin. Although the method avoids the use of metal catalysts, the method has high requirements on the purity of the raw material lactide, and conditions and process requirements in the synthesis process are relatively harsh and complex, the production period is long, and the yield is low. In addition, in the prior art, the purification of polylactic acid needs to consume a large amount of organic solvent and generates a large amount of waste liquid, so that the production cost is increased, and the environmental benefit is low.

Therefore, there is a need to develop an eco-friendly and efficient polylactic acid synthesis process to obtain a pharmaceutical grade polylactic acid material with high purity, regular molecular weight, low metal residue, and even no metal residue.

Disclosure of Invention

The invention aims to provide a method for preparing polylactic acid, which takes lactic acid as a raw material and adopts a non-metal catalyst, and can provide a pharmaceutical grade polylactic acid material with high purity, regular molecular weight, low metal residue and even no metal residue in a green and high-efficiency manner.

The above object of the present invention is achieved by the following means.

The invention provides a method for preparing polylactic acid, which comprises the following steps:

(a) prepolymerizing lactic acid in the presence of a molecular weight regulator;

(b) polycondensing the prepolymerized product in the presence of a catalyst to obtain the polylactic acid;

the catalyst is selected from protonic acid compounds.

Preferably, the method further comprises the step of dehydrating the lactic acid prior to step (a).

Preferably, the dehydration step is such that the lactic acid has a water content of < 2 wt.%.

Preferably, the dehydration step is performed at a temperature of 110 ℃ to 130 ℃ and a vacuum degree of-0.08 MPa to-0.1 MPa.

Preferably, the temperature of the dehydration step may be selected from 110 ℃, 115 ℃, 118 ℃, 120 ℃, 122 ℃, 125 ℃, 128 ℃, 129 ℃, 130 ℃, and any point within a range consisting of any two of the above points.

Preferably, the degree of vacuum of the dehydration step may be selected from-0.08 MPa, -0.09MPa, -0.1MPa, and any point within the range of any two of the above.

Preferably, the protonic acid compound is selected from at least one of sulfuric acid, sodium dodecylbenzenesulfonate, p-toluenesulfonic acid and acetic acid.

Preferably, the protonic acid compound is sulfuric acid.

Preferably, the catalyst is used in an amount of 0.01 wt.% to 0.15 wt.%. More preferably, the catalyst is used in an amount of 0.01 wt.% to 0.1 wt.%. The amount of catalyst used in the present invention is calculated based on the amount of the prepolymerized product unless otherwise specified.

Preferably, the lower limit of the amount of catalyst used is independently selected from the group consisting of 0.01 wt.%, 0.02 wt.%, 0.03 wt.%, 0.05 wt.%, 0.08 wt.%, 0.09 wt.%, 0.1 wt.%, 0.12 wt.%, 0.14 wt.%, 0.15 wt.%, and any point within the range of any two of the foregoing.

Preferably, the upper limit of the amount of catalyst used is independently selected from the group consisting of 0.02 wt.%, 0.04 wt.%, 0.06 wt.%, 0.08 wt.%, 0.09 wt.%, 0.1 wt.%, 0.12 wt.%, 0.14 wt.%, 0.15 wt.%, and any point within the range of any two of the foregoing.

Preferably, the prepolymerization is carried out at a temperature of 140 ℃ to 150 ℃ and a vacuum degree of-0.08 MPa to-0.1 MPa.

Preferably, the temperature of the prepolymerization can be selected from any value within a range of 140 ℃, 141 ℃, 142 ℃, 143 ℃, 144 ℃, 145 ℃, 146 ℃, 147 ℃, 148 ℃, 149 ℃, 150 ℃ and any two of the above values.

Preferably, the degree of vacuum of the prepolymerization may be selected from-0.08 MPa, -0.09MPa, -0.1MPa, and any value within a range consisting of any two of the above values.

Preferably, the prepolymerization is carried out for 1 to 3 hours.

Preferably, the molecular weight regulator is selected from phosphoric acid or lactic acid.

Preferably, the molecular weight regulator is used in an amount of 0.01 wt.% to 0.1 wt.%. Unless otherwise specified, the amount of the molecular weight modifier used in the present invention is calculated based on the amount of the starting lactic acid.

Preferably, the polycondensation is carried out at a temperature of 150 ℃ to 170 ℃ and a vacuum of-0.08 MPa to-0.12 MPa.

Preferably, the polycondensation is carried out at a temperature of 160 ℃ to 170 ℃ and a vacuum of-0.1 MPa.

Preferably, the polycondensation is carried out for 3 to 6 hours.

Preferably, the polycondensation is carried out in the presence of a protective gas.

Preferably, the protective gas may be selected from nitrogen and inert gases such as helium, neon, argon.

Preferably, the method further comprises the step of purifying the polylactic acid after step (b); the purification step comprises dissolving the polycondensation product with a good solvent and then precipitating out with a poor solvent.

Preferably, the good solvent is selected from at least one of acetone and chloroform; the poor solvent is at least one selected from water, ethanol and methanol.

Preferably, the purification step comprises dissolving the polylactic acid with acetone, and then precipitating with water and ethanol.

Preferably, in the purification step, the dissolution-precipitation operation may be repeated a plurality of times.

Preferably, the purified polycondensation product may be further dried and packaged.

Preferably, the polycondensation product may be vacuum dried at 25 ℃ to 50 ℃.

In a preferred embodiment of the present invention, the present invention provides a method for preparing polylactic acid comprising the steps of:

dehydrating the raw material polylactic acid to ensure that the water content of the lactic acid is less than or equal to 2 wt.%;

prepolymerizing lactic acid in the presence of a molecular weight regulator;

polycondensing the prepolymerized product in the presence of a catalyst to obtain polylactic acid;

and purifying the polylactic acid product, wherein the polylactic acid product is dissolved by using a good solvent and then separated out by using a poor solvent.

In a preferred embodiment of the present invention, the dehydration step is performed under the conditions of a temperature of 110 to 130 ℃ and a vacuum of-0.08 MPa to-0.1 MPa.

Preferably, the dehydration step may be performed by means of rotary evaporation.

Preferably, the dehydration step may be performed as follows: in a D-level environment, measuring lactic acid (the content is 85 wt.% to 90 wt.%), placing the lactic acid in a reaction flask of a rotary evaporator, and heating the lactic acid to 120-130 ℃. The vacuum degree is controlled to be-0.08 MPa to-0.1 MPa, and the rotary evaporation is carried out for 1 to 2 hours to remove a large amount of free moisture in the lactic acid.

In the present invention, the dehydration step only dehydrates the raw lactic acid, removing as much as possible 10 wt.% to 15 wt.% of the water in the raw lactic acid. The process is carried out at a low temperature of 110 ℃ to 130 ℃, no catalyst is used, and the dehydration reaction in molecules or between molecules is hardly involved in the dehydration process. The rotary evaporation dehydration is adopted, the dehydration efficiency is higher than that of magnetic stirring, and the dehydration time is shorter. Therefore, it is considered that only lactic acid and a very small amount of oligomer are present in the system after the dehydration treatment, and the polycondensation reaction in the later stage is facilitated. In addition, only the free water is dehydrated, and the condensed water in the collecting bottle is weighed, so that the dehydrating effect can be accurately evaluated and controlled. The dehydration step can completely remove free water in the lactic acid, which eliminates the adverse effect of the free water on the later-stage polycondensation reaction, and enables the forward reaction to be carried out more smoothly.

In a preferred embodiment of the present invention, the prepolymerization is carried out in the presence of a molecular weight regulator. The molecular weight regulator is selected from phosphoric acid or lactic acid. The dosage of the molecular weight regulator is 0.01 wt.% to 0.1 wt.%. The prepolymerization is carried out under the conditions that the temperature is 140-150 ℃ and the vacuum degree is-0.08 MPa-0.1 MPa. The prepolymerization is carried out for 1-3 hours.

Preferably, the prepolymerization can be carried out as follows: in a class D environment, 0.01 wt.% to 0.1 wt.% of a molecular weight regulator (e.g., phosphoric acid) is added with stirring and heated to 140 ℃ to 150 ℃. And installing a cooling sleeve, controlling the temperature of the condensing pipe at-10-0 ℃, and controlling the vacuum degree at-0.08 MPa to-0.1 MPa for rotary evaporation for 1-3 hours.

In the present invention, a prepolymerization step is added before polycondensation, and a molecular weight regulator is added. The oligomer provided by the step provides a favorable basis for obtaining polylactic acid with more regular molecular weight and narrower molecular weight distribution through subsequent polycondensation.

In a preferred embodiment of the invention, the polycondensation is carried out in the presence of a catalyst. The catalyst is selected from protonic acid compounds. The protonic acid compound is at least one of sulfuric acid, sodium dodecyl benzene sulfonate, p-toluenesulfonic acid and acetic acid. The dosage of the catalyst is 0.01 wt.% to 0.15 wt.%. The polycondensation is carried out under the conditions that the temperature is 150-170 ℃ and the vacuum degree is-0.08 MPa to-0.12 MPa. And performing polycondensation for 3-6 hours.

In a more preferred embodiment of the invention, the polycondensation is carried out in the presence of a catalyst. The catalyst is sulfuric acid. The dosage of the catalyst is 0.01 wt.% to 0.1 wt.%. The polycondensation is carried out at a temperature of 160 ℃ to 170 ℃ and a vacuum degree of-0.1 MPa. And performing polycondensation for 3-6 hours.

Preferably, the polycondensation may be carried out as follows: adding 0.01 wt.% to 0.1 wt.% of a catalyst (e.g., sulfuric acid, etc.) to the prepolymer product to be polycondensed under stirring in a stage D environment, and heating to 150 ℃ to 170 ℃. Installing a drying tower and a steam receiving device, controlling the temperature of a condensing tube to be less than or equal to minus 20 ℃, controlling the vacuum degree to be minus 0.1MPa, and stirring for reaction. For example, after 3 hours of reaction, samples can be taken to monitor viscosity and molecular weight within the polycondensation system. And judging whether the reaction needs to be continued or not according to whether the molecular weight reaches the required range or not, and stopping the reaction when the molecular weight and the like reach the expected range. For example, the reaction may be carried out for 3 to 6 hours. During the measurement of viscosity and molecular weight, protective gas (such as nitrogen) is introduced for protection.

In the invention, polycondensation is carried out on the basis of prepolymerization, the temperature is slightly increased, and the risk that the color of a high polymer is deepened due to degradation and carbonization of an oligomer at high temperature is avoided.

Installing a drying tower and a steam receiving device, controlling the temperature of a condensing pipe to be less than or equal to minus 20 ℃, and controlling the vacuum degree to be minus 0.1 MPa. The low vacuum ensures that the trace moisture generated by polycondensation is extracted in time. And the condensing pipe, the steam receiving device and the drying tower can be sequentially arranged to ensure that the extracted moisture is timely cooled and received. The drying tower will not be fully absorbed by the water vapour that is cooled and received. The combined device can efficiently capture and absorb water vapor, and effectively avoids water reflux caused by factors such as vacuum degree fluctuation, sampling and the like of the pumped water vapor. Ensuring that the polymerization reaction proceeds smoothly in the forward direction all the time.

The end point of polycondensation can be judged as follows: for example, after 2 hours of reaction, a sample is taken to measure viscosity and molecular weight within the system. The reaction is stopped when the molecular weight etc. reaches the desired range. For example, the reaction may be carried out for 2 to 4 hours. The end point of the polycondensation reaction is judged, and the molecular weight of the final product is accurately controlled according to the determined molecular weight. The problem that the viscosity of the final product is higher due to larger difference (the viscosity difference is 0.1ml/g, and the molecular weight difference is about 110) caused by adopting the intrinsic viscosity to control the reaction end point is avoided.

During the polycondensation, the protection is carried out by introducing protective gas (for example, nitrogen) during the sampling for measuring the viscosity and the molecular weight, and the polymerization reaction product is ensured not to be oxidized.

In the invention, the catalyst adopted by polycondensation is a protonic acid compound, and a metal catalyst (such as organic tin) with high toxicity, which is conventionally used in the prior art, is abandoned, so that the introduction of metal elements which are unfavorable for the medical application, the food application and the like of the polylactic acid in the synthesis stage is avoided.

In a preferred embodiment of the present invention, the polycondensation product is subjected to a purification step comprising dissolving the polycondensation product with a good solvent and then precipitating out with a poor solvent. The good solvent is selected from at least one of acetone and chloroform; the poor solvent comprises at least one of water, ethanol and methanol.

Preferably, the purification step may be performed as follows: in a D-grade environment, after cooling the polycondensation product, the polycondensation product is dissolved by acetone. Slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out. The process may be repeated. Finally, it was dried under vacuum at 45 ℃ to constant weight. And (5) subpackaging to obtain a finished product in a C-level environment.

Alternatively, in a class D environment, the polycondensation product is cooled and then dissolved in acetone. Slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out. After the precipitate is extruded, the precipitate can be dissolved again by acetone, the dissolved matter is poured into 95% ethanol for precipitation, and after the precipitate is extruded, the precipitate is repeatedly washed and extruded by ethanol for a plurality of times. Finally, it was dried under vacuum at 45 ℃ to constant weight. And (5) subpackaging to obtain a finished product in a C-level environment.

In the method of the present invention, the "class C environment" and the "class D environment" refer to environmental conditions according to standards required in each level of "pharmaceutical production quality management standards" (2010 version) in appendix "sterile drugs" clean zone.

In the process of the invention, a small amount of acetone is used for dissolution, and then water and ethanol are used for precipitation. The usage amount of the organic solvent is reduced, the polar impurities are fully removed, a large amount of organic waste liquid is not generated, the purification effect of the finished polylactic acid is good, and the quality meets the requirement of medical application.

The invention has at least the following beneficial effects:

(1) according to the preparation method of the polylactic acid, the raw material is dehydrated in a more efficient dehydration mode, so that the dehydration effect can be more conveniently evaluated and controlled, the adverse effect of free water on the later-stage polycondensation reaction is eliminated, and the forward reaction is more smoothly carried out.

(2) The preparation method of polylactic acid provided by the invention adds a prepolymerization stage before polycondensation, and the stage provides a favorable basis for obtaining polylactic acid with more regular molecular weight and narrower molecular weight distribution by subsequent polycondensation.

(3) The polylactic acid preparation method provided by the invention adopts the non-metal catalyst to catalyze polycondensation at a lower temperature, so that the risks of high polymer degradation at a high temperature and low polymer carbonization to darken the color are avoided, and the introduction of metal elements with high toxicity which are unfavorable to medical and food application occasions and the like in the polylactic acid synthesis stage is avoided.

(4) According to the preparation method of the polylactic acid, the use amount of an organic solvent is reduced in the purification step of the polymer, polar impurities are fully removed, a large amount of organic waste liquid cannot be generated, the purification effect of the finished product polylactic acid is good, and the quality meets the medical application requirements.

(5) The preparation method of polylactic acid provided by the invention can provide the pharmaceutical grade polylactic acid material with high purity, high yield, regular molecular weight, low metal residue and even no metal residue in an environment-friendly and efficient manner.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

In the examples of the present invention, the dehydration degree of the raw material was calculated by a weighing method.

The intrinsic viscosity of the polymerization system was measured by an Ubbelohde viscometer.

The molecular weight and the distribution of the prepolymer/polymer are determined by size exclusion chromatography (general rules of Chinese pharmacopoeia 0514) and calculated by GPC software.

The content of lactide, the microorganism, the organic solvent residue and the heavy metal residue in the polylactic acid are respectively measured by adopting the following instruments/methods:

residual solvent: measurement by reference to the residual solvent measurement method (third method 0861 general rule of Chinese pharmacopoeia);

microorganisms: measuring by reference (general rule of Chinese pharmacopoeia 1105);

bacterial endotoxin: measuring by reference (general rule 1143 of Chinese pharmacopoeia);

heavy metals: measuring by reference (the second method of Chinese pharmacopoeia general rule 0821);

tin: measuring according to Chinese pharmacopoeia general rule 0411;

lactide: measuring by reference (general rule 0521 of Chinese pharmacopoeia);

residue on ignition: measuring according to the general rule 0841 of Chinese pharmacopoeia;

the indexes of lactide content, microorganism, organic solvent residue and heavy metal residue in the polylactic acid are carried out according to the standard of enterprise standard PQS-RD 024.

Example 1Dehydration treatment of materials

1L of DL-lactic acid (85 wt.%) was taken and placed in a reaction flask of a rotary evaporator, and heated, rotary evaporated under reduced pressure to remove water. The dehydration conditions and results are summarized in table 1. In which dehydration experiment 1^#And dehydration experiment 2^#The dehydration effect of the dehydration treatment meets the requirement, and the moisture content of the lactic acid is reduced to below 2 wt.%. Dehydration experiment 2^#Shorter treatment time than in dehydration experiment 1^#The dewatering effect is better.

TABLE 1 dehydration treatment conditions and results

Example 2Pre-polymerization

A dehydrated 0.5 liter lactic acid obtained in example 1 was taken, and a molecular weight modifier was added to a reaction flask, a condensing device was provided, and the temperature of condensation was controlled to-10 ℃ to 0 ℃ and prepolymerization was carried out under a selected degree of vacuum with stirring. The number of each prepolymerization experiment and the corresponding prepolymerization conditions and results are given in Table 2. Comparative experiment 10^#As a comparative example, the polycondensation was carried out by directly adding the catalyst without prepolymerization.

TABLE 2 prepolymerization/comparative polycondensation conditions and results

The intrinsic viscosity is one of important parameters of lactic acid prepolymerization degree, and has important influence on the regulation and control of the subsequent polycondensation process and the polycondensation effect. Usually, when the intrinsic viscosity value of the prepolymerization system is more than 7ml/g, the subsequent polycondensation is more facilitated to obtain the polylactic acid product which is more in accordance with the medical grade.

In this embodiment, the intrinsic viscosity of the system is adjusted by controlling the temperature, vacuum degree, prepolymerization time, molecular weight regulator and the amount thereof. As can be seen from the results in Table 2, under the experimental conditions of this example, the intrinsic viscosity of the system can be controlled to be 7ml/g or more in a short (2 hours) prepolymerization time.

As can be seen from the results of comparative experiment, when the prepolymerization was carried out under a vacuum of-0.07 MPa, the prepolymerization time was within 2 hours (comparative experiment 7)^#Comparative experiment 8^#) The intrinsic viscosity of the system was 5.8ml/g, 6.1ml/g, respectively, and did not reach the desired 7ml/g, but the prepolymerization time was continued for a further 7 hours (comparative experiment 9)^#) When the intrinsic viscosity of the system reached prepolymerization experiment 3^#And 5^#A level of little difference. However, greatly prolonging the prepolymerization time not only increases the overall reaction period for producing polylactic acid, but also increases the risk of side reactions such as carbonization, thermal degradation, oxidation and the like in the system, thereby increasing the production cost, and being not beneficial to improving the production efficiency and ensuring the product quality.

Example 3Polycondensation

To the prepolymerized product obtained in prepolymerization experiment 4 of example 2, a catalyst was added, a condensing unit was equipped, and the condensation temperature was controlled at-25 ℃ and polycondensation was stirred under the selected degree of vacuum. The number of each polycondensation experiment and the corresponding polycondensation conditions and results are shown in Table 3.

Comparative experiment 19^#、20^#、21^#、22^#、23^#Comparative experiment 10 in example 2^#The product of (a) is used as a starting material for further polycondensation.

Comparative experiment 22^#: comparative experiment 10 from example 2^#A quarter of the amount of the product obtained, stirring0.4g of catalyst stannous octoate is added under stirring, and the temperature is raised to 200 ℃. And installing a drying tower and a steam receiving device, controlling the temperature of a condensing pipe to be 25 ℃ below zero and the vacuum degree to be 0.1MPa below zero, and stirring for reaction for 3 hours.

Comparative experiment 23^#: taking 1.0 liter of DL-lactic acid (85 percent), placing the DL-lactic acid in a reaction bottle, heating the DL-lactic acid to 130 ℃ in an oil bath, controlling the vacuum degree to be minus 0.06MPa, and reacting for 1.5 hours. Adding 0.4g of catalyst stannous octoate while stirring, and heating to 200 ℃. And installing a drying tower and a steam receiving device, controlling the temperature of a condensing pipe to be 25 ℃ below zero and the vacuum degree to be 0.1MPa below zero, and stirring for reaction for 3 hours. The final polycondensation product was slightly yellow in color.

Comparative experiment 24^#: 100g of DL-lactide was added to the three-necked flask. Magnetic stirring was started and the rotational speed was set to around 250 rpm. The constant temperature oil bath was turned on and the batch was heated to 160 ℃. When the temperature of the material reached 160 ℃. 0.05g of stannous octoate is weighed, and 0.6g of toluene is added to be stirred and dissolved, so that the catalyst solution is obtained. About 1.0g of lactic acid and 0.5g of catalyst solution (0.04 g of stannous octoate) were added sequentially. After the nitrogen gas is started to react for 8 hours, a sample is taken to measure the viscosity.

TABLE 3 conditions and results of polycondensation/comparative polycondensation

In Table 3, "3 + 1" indicates that the reaction was continued for 1 hour after the sampling after 3 hours of the reaction.

From the results in table 3, it can be found that:

(1) after prepolymerization, polycondensation is carried out (for example, polycondensation experiment 11)^#Polycondensation experiment 18^#) The polylactic acid obtained is directly polycondensed (comparative experiment 19)^#Comparative experiment 24^#) The obtained polylactic acid is much narrower, and the molecular weight distribution of the polylactic acid can be controlled within 1.5;

(2) when the polylactic acid is applied to medicines, a polylactic acid product with the molecular weight of 2-3 ten thousand and the intrinsic viscosity of 20-30 ml/g can better play a role of long-acting slow release; for example, the polylactic acid product with the molecular weight of 2-3 ten thousand and the intrinsic viscosity of 20-30 ml/gThe sustained-release material can be used as a controlled-release material of a sustained-release preparation of polypeptide and other medicaments for 3 months, and can also be used as a medical material matrix for 2-3 months; polycondensation experiment 13^#、14^#、18^#Compared with other polycondensation experiments, if the molecular weight of the polylactic acid is expected to be controlled to be between 2 and 3 ten thousand and the intrinsic viscosity is between 20 and 30ml/g, the polycondensation is better carried out under the conditions that the temperature is between 160 and 170 ℃, the vacuum degree is minus 0.1MPa and the sulfuric acid is used as a catalyst;

(3) polycondensation experiment 11^#And polycondensation experiment 12^#In comparison, the nitrogen is introduced to protect and then the reaction is continued in the sampling process, so that the more regular molecular weight distribution and the higher molecular weight polylactic acid can be obtained; comparative experiment 19^#Comparative experiment 20^#Comparison, finding comparative experiment 20^#The molecular weight of the polylactic acid obtained in the process is obviously lower than that of the comparative experiment 19^#Molecular weight of (1), which may be attributed to polylactic acid in comparative experiment 20^#In which degradation occurred, and comparative experiment 19^#The nitrogen is introduced, so that the possibility of degrading the polylactic acid with higher molecular weight is effectively prevented;

(4) comparative experiment 24^#Using DL-lactide as a raw material, and preparing polylactic acid by adopting stannous octoate catalysis to perform ring-opening polymerization under normal pressure; however, the molecular weight of the polymer reached the molecular weight of the polycondensation experiment 11 only after a reaction period of up to 8 hours^#Polycondensation experiment 12^#Comparative level, but molecular weight distribution ratio polycondensation experiment 11^#Polycondensation experiment 12^#Much wider;

(5) comparative experiment 22^#The starting material used was lactic acid treated in example 1 using the dehydration step of the present invention, and comparative experiment 23^#The raw material (A) is not dehydrated; comparative experiment 22^#Comparative experiment 23^#Comparative experiment 23, which was found not to be dehydrated^#The polycondensation product has low yield and the molecular weight is obviously lower than that of the comparative experiment 22^#；

(6) Comparative experiment 22^#Comparative experiment 23^#The polylactic acid obtained in (1) has an inherent color in appearance because ofCondensation at higher temperatures can result in charring of the polylactic acid, which not only affects the appearance of the final polymer, but also is detrimental to the conversion of the monomer or oligomer and the final molecular weight increase.

Example 4Purification of polymers

Purification experiment 25^#: polycondensation experiment 12^#After the reaction was completed, it was cooled and dissolved in 500ml of acetone. 100ml of the dissolved substance is taken and slowly poured into water for injection at 60-80 ℃, and the polymer is separated out by stirring. When the water for injection is turbid, the water for injection is replaced until the polymer is completely precipitated. Squeezing, dissolving in 100ml acetone again, precipitating with 500ml 95% medicinal ethanol, squeezing, washing with ethanol repeatedly, and squeezing for 3 times. Finally, vacuum drying is carried out at the temperature of 45 ℃ to obtain 38g of finished product polylactic acid. The yield thereof was found to be 91%. And (3) measuring the lactide content, the microorganism, the organic solvent residue and the heavy metal residue in the polymer.

Purification experiment 26^#: the purification procedure and purification experiment 25^#The difference lies in that firstly the polylactic acid is precipitated by ethanol and then the polylactic acid is precipitated by water for injection.

Comparative experiment 27^#: polycondensation experiment 12^#After the reaction was completed, it was cooled and dissolved in 500ml of acetone. 100ml of the dissolved substance is taken and slowly poured into water for injection at 60-80 ℃, and the polymer is separated out by stirring. When the water for injection is turbid, the water for injection is replaced until the polymer is completely precipitated. Squeezing, dissolving in 100ml acetone again, slowly pouring into 60-80 deg.C water for injection, stirring to precipitate, and repeatedly washing with water for injection for 3 times. Finally, vacuum drying is carried out at the temperature of 45 ℃ to obtain 35g of finished product polylactic acid. The yield thereof was found to be 87%. And (3) measuring the lactide content, the microorganism, the organic solvent residue and the heavy metal residue in the polymer.

Comparative experiment 28^#: polycondensation experiment 12^#After the reaction was completed, it was cooled and dissolved in 500ml of acetone. 100ml of the dissolved substance is taken and slowly poured into 95 percent medicinal ethanol, and the polymer is separated out by stirring. When the 95% medicinal ethanol is turbid, the 95% medicinal ethanol is replaced until the polymer is completely separated out. Squeezing, and dissolving in 100ml of water againAnd (3) pouring the dissolved substance into 500ml of 95% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding the precipitate for 3 times by using ethanol, and finally performing vacuum drying at 45 ℃ to obtain 34g of finished polylactic acid. The yield thereof was found to be 84%. And (3) measuring the lactide content, the microorganism, the organic solvent residue and the heavy metal residue in the polymer.

Comparative experiment 29^#: comparative experiment 22^#After the polycondensation reaction is finished, cooling, dissolving in 500ml of trichloromethane, taking 100ml of dissolved matter, slowly pouring into injection water at 60-80 ℃, and stirring to separate out the polymer. When the water for injection is turbid, the water for injection is replaced until the water for injection is completely precipitated. Squeezing, dissolving in 100ml acetone again, precipitating with 500ml 95% medicinal ethanol, squeezing, washing with ethanol repeatedly, and squeezing for 3 times. Finally, vacuum drying is carried out at the temperature of 45 ℃ to obtain 180g of finished product polylactic acid. The yield thereof was found to be 90%. And (3) measuring the lactide content, the microorganism, the organic solvent residue and the heavy metal residue in the polymer.

Comparative experiment 30^#: comparative experiment 23^#After the polycondensation reaction, the mixture is cooled, dissolved in 1.8L of chloroform, slowly poured into 9L of 95% medicinal ethanol for precipitation, and stirred to separate out the polymer. When turbidity appears, the ethanol is replaced until all the polymer is separated out. Extruding, repeatedly washing the precipitate with ethanol for 3 times, and vacuum drying at 45 deg.C to obtain 780g of polylactic acid. The yield thereof was found to be 78%. And (3) measuring the lactide content, the microorganism, the organic solvent residue and the heavy metal residue in the polymer.

Comparative experiment 31^#: comparative experiment 24^#After the polycondensation reaction is finished, cooling, crushing, pouring into cooled water for injection, and continuously crushing for 2 minutes. Pouring the crushed polylactic acid into a screen, washing with cold injection water, and performing suction filtration. Finally, vacuum drying is carried out at the temperature of 45 ℃ to obtain 92g of finished product polylactic acid. The yield thereof was found to be 92%. And (3) measuring the lactide content, the microorganism, the organic solvent residue and the heavy metal residue in the polymer.

Purification experiment 25^#Purification experiment 26^#Comparative experiment 27^#Comparative experiment 31^#The purification conditions and yields of (A) are summarized in Table 4, the purification of the finished polylactic acidThe detection indices are summarized in table 5.

TABLE 4 purification conditions and yields

TABLE 5 detection index for polylactic acid

From the results in tables 4 and 5, it can be found that purification experiment 25^#And purification experiment 26^#The purification step provided by the invention is adopted for purification, and the indexes of lactide content, microorganism, organic solvent residue and heavy metal residue in the obtained polylactic acid finished product all meet the standard.

Comparative experiment 27^#Although ethanol is avoided, the injection water has poor capacity of removing lactide and impurities, so that the index of the lactide residue in the final polylactic acid finished product does not meet the standard.

Comparative experiment 28^#Although each main index of the finished product reaches the set standard, more ethanol solvent is used, so that the waste liquid amount is more than that of the purification experiment 25^#Twice as much.

Comparative experiment 29^#～31^#Stannous octoate is used as a catalyst, so that the content of tin in the polylactic acid finished product can not reach the set standard. The purification method has poor capability of removing lactide and heavy metals and also cannot reach the set standard.

Synthesis of the indices of the polylactic acids of the respective products, purification experiment 25^#And purification experiment 26^#All indexes of the obtained polylactic acid finished product reach the standard, only a small amount of acetone, water and ethanol are involved in the purification process, a large amount of waste liquid is not generated, and the environmental benefit is high.

The foregoing is merely exemplary of the invention and is not intended to limit the invention in any manner. Although the present invention has been described with reference to preferred embodiments, it is not intended to be limited thereto. Those skilled in the art should appreciate that they can readily use the disclosed conception and specific embodiments as a basis for designing or modifying other structures for carrying out the same purposes of the present invention without departing from the scope of the invention as defined by the appended claims.