KR20220076235A - Method for preparation of block copolymer - Google Patents

Abstract

A first step of the present invention is to prepare a polylactide (PLA) oligomer including hydroxy groups at both ends by ring-opening polymerization of lactide in the presence of an initiator and a catalyst; a second step of adjusting unreacted lactide in the product of the first step to 0 parts by weight or more and 0.5 parts by weight or less, based on 100 parts by weight of the polylactide oligomer; and a third step of ring-opening polymerization of glycolide at both ends of the polylactide oligomer, wherein unreacted lactide is contained in the product in the first step by weight based on 100 parts by weight of the polylactide oligomer. It relates to a method for preparing a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA), which is included in more than parts and not more than 30 parts by weight. The manufacturing method of the present invention can provide a block copolymer with improved strength and aesthetics sufficient for use as a resin for spinal fixation due to high crystallinity and high melting point.

Description

Method for producing a block copolymer {METHOD FOR PREPARATION OF BLOCK COPOLYMER}

The present invention relates to a method for preparing a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA). More specifically, the manufacturing method of the present invention can provide a block copolymer with improved strength and aesthetics sufficient for use as a resin for spinal fixation due to high crystallinity and high melting point.

Polymer materials can be used in various industrial fields, such as polymer materials for electrical and electronic applications, optical functional polymer materials, and medical polymer materials, and the scope of application is gradually expanding.

According to these industrial demands, polymer materials having various functions are being researched and developed.

In particular, the biodegradable polymer material absorbable into the human body does not have corrosion problems compared to metal and ceramic materials, does not require a separate surgical removal operation after healing of bones and tissues, and is gradually decomposed as the wound is healed so that the newly created tissue is gradually sufficient. It has the advantage of being able to help it to have function and strength. In addition, there is a problem of stress shielding in that the strength of fracture/wound sites cannot be fully recovered because metals and ceramics are too strong than the strength of living tissues. It is the most widely studied due to its excellent physical properties and hydrolysis properties.

Among these aliphatic polyesters, biodegradable polymer materials such as polylactic acid (PLA), polyglycolic acid (PGA), and PLA-co-PGA, which are random copolymers of these aliphatic polyesters, are used for spinal fixation devices. application is being attempted.

Among these aliphatic polyesters, polylactic acid has a bioabsorption rate of more than 24 months, and is widely used as a material for orthopedic and plastic surgery tissue fixation such as rods, pins, screws, and fixing plates. A large amount of must be added, and in this case, the melt viscosity increases, which entails a problem in that melt workability is lowered during actual implant processing. In addition, although polyglycolic acid has excellent strength, melt processability is low and the biodegradation rate is too fast. In addition, in the case of PLA-co-PGA, which is a random copolymer of these, usually mixed with monomers and polymerized, and its strength is weak, so its utility as a drug delivery agent is limited.

In order to solve the above problems, there is a need for research on a new biodegradable biodegradable polymer material having good melt processability and excellent strength.

Republic of Korea Patent Publication No. 10-1281834

An object of the present invention is to provide a block copolymer with improved strength and aesthetics sufficient for use as a resin for spinal fixation due to high crystallinity and high melting point.

An exemplary embodiment of the present invention includes a first step of preparing a polylactide (PLA) oligomer including a hydroxyl group at both ends by ring-opening polymerization of lactide in the presence of an initiator and a catalyst; a second step of adjusting unreacted lactide in the product of the first step to 0 parts by weight or more and 0.5 parts by weight or less, based on 100 parts by weight of the polylactide oligomer; and a third step of ring-opening polymerization of glycolide at both ends of the polylactide oligomer, wherein unreacted lactide is contained in the product in the first step by weight based on 100 parts by weight of the polylactide oligomer. It provides a method for preparing a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA), which is included in more than parts and not more than 30 parts by weight.

The block copolymer prepared according to the production method of the present invention has a high crystallinity and a high melting point, so that it has sufficient strength to be used as a resin for fixing the spine.

In addition, the block copolymer prepared according to the production method of the present invention can improve the aesthetics of the block copolymer and prevent deterioration of physical properties by controlling the content of unreacted lactide.

1 is a diagram illustrating the analysis of polylactide oligomers after the second step of Examples 1, 2, Comparative Example 2 and Comparative Example 3 using a scanning electron microscope (SEM).

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described below in detail in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms, and only these embodiments allow the disclosure of the present invention to be complete, and common knowledge in the art to which the present invention pertains It is provided to fully inform those who have the scope of the invention, and the present invention is only defined by the scope of the claims. Like reference numerals refer to like elements throughout.

Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used with the meaning commonly understood by those of ordinary skill in the art to which the present invention belongs. In addition, terms defined in a commonly used dictionary are not to be interpreted ideally or excessively unless clearly defined in particular.

In the present specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.

Hereinafter, the present invention will be described in detail.

An exemplary embodiment of the present invention includes a first step of preparing a polylactide (PLA) oligomer including a hydroxyl group at both ends by ring-opening polymerization of lactide in the presence of an initiator and a catalyst; a second step of adjusting unreacted lactide in the product of the first step to 0 parts by weight or more and 0.5 parts by weight or less, based on 100 parts by weight of the polylactide oligomer; and a third step of ring-opening polymerization of glycolide at both ends of the polylactide oligomer, wherein unreacted lactide is contained in the product in the first step by weight based on 100 parts by weight of the polylactide oligomer. It provides a method for preparing a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA), which is included in more than parts and not more than 30 parts by weight.

The manufacturing method according to an exemplary embodiment of the present invention provides a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA). In this case, compared to the random copolymer of polylactide (PLA)-co-polyglycolide (PGA), the crystallinity is large and the melting point is high, so it has sufficient strength to be used as a resin for fixing the spine.

In the third step, in the case of polylactide oligomer containing hydroxyl groups at both ends, the melting rate is slower than that of glycolide, so it cannot be melted and remains in the reactor. There is a problem that causes According to the manufacturing method according to an exemplary embodiment of the present invention, in the first step, unreacted lactide of the product in the first step is 5 parts by weight or more and 30 parts by weight or less based on 100 parts by weight of the polylactide oligomer. Follow the steps. As the content of the unreacted lactide increases in the product of the first step, pores are formed in the polymer to decrease the density of the polylactide oligomer and increase the specific surface area, and in the third step, the polylactide By increasing the rate of succulents, dark spots in the final product can be minimized. However, after the first step, if the content of unreacted lactide in the product is less than 5 parts by weight based on 100 parts by weight of the polylactide oligomer, the density is too high and the specific surface area is reduced so that dark spots of the final product are reduced. can be increased. In addition, after the first step, when the content of unreacted lactide in the product exceeds 30 parts by weight based on 100 parts by weight of the polylactide oligomer, the melting point of the polylactide oligomer is low and unreacted lactide is The second step of removing cannot be performed.

In the exemplary embodiment of the present specification, the control of the content of unreacted lactide in the product after the first step may be due to the ratio of the initiator to the lactide, the reaction temperature, and the amount of catalyst.

In one embodiment of the present invention, the lactide may be L-lactide.

In another exemplary embodiment, the catalyst is sufficient as long as it is a catalyst generally used in the art, but is not limited thereto, for example, lead oxide, calcium oxide, aluminum oxide, iron oxide, calcium chloride, zinc acetate, paratoluene sulfate phonic acid, stannous chloride, stannous sulfate, stannous oxide, stannous oxide, stannous octylic acid, tetraphenyl tin, tin powder, titanium tetrachloride, and the like. In one embodiment, it is appropriate to use a tin-based compound such as tin octylate.

In an exemplary embodiment of the present invention, the initiator is a material that initiates a polymerization reaction, and any initiator used in the art is sufficient, but is not limited thereto, but non-limiting examples include alcohols. In one embodiment, the initiator may be ethylene glycol.

In an exemplary embodiment of the present invention, the content of unreacted lactide may be due to the content of the initiator, the reaction temperature and/or the content of the catalyst. Therefore, in the first step, it is important to properly control the content of the initiator, the reaction temperature and/or the content of the catalyst.

In one embodiment, the first step may be performed at a temperature of 170 °C or higher and 190 °C or lower. When the reaction temperature is less than 170° C., the reaction initiation does not occur or it takes a long time to obtain a polylactide oligomer, and when the reaction temperature exceeds 190° C., thermal decomposition of the polymer occurs.

In another exemplary embodiment, in the first step, the content of the catalyst is 0.005 parts by weight or more and 0.013 parts by weight or less, based on 100 parts by weight of lactide. When the content of the catalyst in the first step is less than 0.005 parts by weight based on 100 parts by weight of lactide, no reaction initiation occurs, and when it exceeds 0.013 parts by weight, the catalyst remaining in the polymer causes a problem in subsequent cytotoxicity can do.

In one embodiment, the content of the catalyst in the first step is 50 ppm or more and 130 ppm or less. If the content of the catalyst is less than 50 ppm, reaction initiation does not occur, and if it exceeds 130 ppm, it may cause a problem in subsequent cytotoxicity due to the catalyst remaining in the polymer.

In one embodiment, the weight ratio of the lactide to the initiator is 400:1 or more and 600:1 or less. When the weight ratio of lactide and initiator is within the above range, the molecular weight of polylactide in the block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA) is 20,000 g/mol More than or equal to 40,000 g/mol or less, the content range can be adjusted by those skilled in the art according to the required molecular weight and physical properties of the final block copolymer.

In an exemplary embodiment of the present invention, after the second step, the density of the polylactide oligomer may be 0.5 g/cm ³ or more and 1 g/cm ³ or less. The density is caused by adjusting the content of the unreacted lactide in the product in the first step. Specifically, when the content of unreacted lactide in the product after the first step and before the second step is less than 5 parts by weight based on 100 parts by weight of the polylactide oligomer, the amount of the polylactide oligomer after the second step is The density may be about 1.2 g/cm ³ . On the other hand, when the content of unreacted lactide in the product after the first step and before the second step is 5 parts by weight or more and 30 parts by weight or less, based on 100 parts by weight of the polylactide oligomer, unreacted lactide is After the removal of the second step, it may have a density in the above range. That is, the unreacted lactide may form pores in the polylactide oligomer after the second step to lower the density and increase the surface area.

In one embodiment, the polylactide oligomer prepared in the first step may be prepared in the form of pellets or cut to a size of 2 mm to 3 mm. In this case, it may be easy to control unreacted lactide in the second step and polymerization in the third step.

In one embodiment, the first step may be performed for a reaction time of about 240 minutes to reach equilibrium between lactide and polylactide oligomer, but depending on the content of the catalyst, the reaction temperature, the content of the initiator, etc. can be adjusted.

In one embodiment of the present invention, the reaction tank in the first step may use a reaction tank generally used in the art, for example, there is a stirred tank or a tubular type, impeller (impeller), spider impeller (spider) impeller), may be a reaction tank equipped with a stirrer such as a paddle impeller (paddle impeller). In addition, it may be a different stirrer or a different type of reactor depending on the viscosity.

In an exemplary embodiment of the present invention, the second step of adjusting unreacted lactide in the product of the first step to 0 parts by weight or more and 0.5 parts by weight or less based on 100 parts by weight of the polylactide oligomer include When the content of the unreacted lactide is more than 0.5 parts by weight, in the third step, the unreacted lactide serves as a terminator, so that polyglycolide (PGA)-polylactide (PLA)-polyglycol It may interfere with the preparation of block copolymers of lead (PGA).

In an exemplary embodiment of the present invention, the second step is performed at a temperature of 100 °C or higher and 120 °C or lower. When the second step is performed at a temperature of less than 100° C., the removal of lactide is not easy, and when it exceeds 120° C., the polylactide oligomer may be melted.

In one embodiment, the second step may be performed at a pressure of 1 torr or less. In one embodiment, the second step may be performed at a pressure of 0.2 Torr or more and 1 Torr or less. In the second step, the pressure is reduced with a high-temperature vacuum to remove residual monomers (unreacted lactide), and unreacted lactide is contained in an amount of 0 parts by weight or more, 0.5 parts by weight based on 100 parts by weight of the polylactide oligomer. can be adjusted below.

In another exemplary embodiment, in the second step, the content of unreacted lactide in the product of the first step is adjusted to 0.5 parts by weight or less based on 100 parts by weight of the polylactide oligomer. It may be carried out, preferably for about 12 hours or more, and more preferably for 16 hours or more.

In an exemplary embodiment of the present invention, the molar ratio of lactide to glycolide in the reaction is 1:9 or more and 9:1 or less. However, the molar ratio of lactide and glycolide may be adjusted according to the required physical properties of the block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA).

In another exemplary embodiment, the third step is performed at a temperature of 180 °C or higher and 230 °C or lower. In one embodiment, the third step may be performed while increasing the reaction temperature stepwise in a temperature range of 180 °C or higher and 230 °C or lower. Specifically, the third step may be performed while increasing the reaction temperature stepwise at a rate of about 1 °C/min in a temperature range of 180 °C or higher and 230 °C or lower. If the third step is performed at a temperature of less than 180 ℃, there is a problem that the reaction does not start or the reaction time is very long. In addition, when the third step is performed at a temperature exceeding 230 ℃, poly At a temperature higher than the melting point (T _m ) of the block copolymer of glycolide (PGA)-polylactide (PLA)-polyglycolide (PGA), thermal decomposition may occur.

In an exemplary embodiment of the present invention, the third step may be performed in the presence of a catalyst. In one embodiment, the catalyst in the third step may be the same as or different from the catalyst used in the first step, and may be the same as examples of the catalyst used in the first step independently.

In one embodiment, the content of the catalyst in the third step may be 0.005 parts by weight based on 100 parts by weight of glycolide.

In one exemplary embodiment, the third step may be performed for a time of 1 hour or more and 24 hours or less, but may be adjusted according to catalyst content, reaction temperature, and the like.

Hereinafter, examples will be given to describe the present invention in detail. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention is not to be construed as being limited to the embodiments described below. The embodiments of the present specification are provided to more completely explain the present invention to those of ordinary skill in the art.

Example 1

Ethylene glycol (initiator; Sigma-Aldrich) and tin octoate (Tin(II)2-ethylhexanoate; catalyst; Sigma-Aldrich) 70ppm (0.007 parts by weight relative to 100 parts by weight of lactide) in the reactor In the presence of L-lactide (M/I ratio) of lactide and initiator of 600:1 was added to L-lactide (L-Lactide; Medichem), and after replacing with nitrogen for 1 hour, the polylactide oligomer was polymerized. Thereafter, the pressure was reduced at 120° C. and 1 torr or less for 16 hours, lactide and glycolide were added to the reactor in a molar ratio of 30: 70, and tin octoate (Tin (II) 2-ethylhexanoate; catalyst) ; Sigma-Aldrich Co.) 50ppm as a catalyst, replaced with nitrogen for 1 hour, and then the reaction temperature was raised stepwise from 180℃ to 215℃ to polyglycolide (PGA)-polylactide (PLA)-polyglycolide A block copolymer of (PGA) was prepared.

Example 2 and Comparative Examples 1 to 4

Polyglycolide (PGA)-polylactide (PLA) in the same manner as in Example 1, except that in Example 1, the ratio of lactide and initiator, reaction temperature, and catalyst amount were as shown in Table 1 below. )-A block copolymer of polyglycolide (PGA) was prepared.

First stage polymerization conditions Lactide: Initiator Reaction temperature (℃) Catalyst amount (parts by weight of catalyst relative to 100 parts by weight of lactide) Example 1 600:1 180 0.007 Example 2 400:1 180 0.007 Comparative Example 1 600:1 160 0.007 Comparative Example 2 200:1 180 0.007 Comparative Example 3 400:1 180 0.014 Comparative Example 4 400:1 180 0.003

As a result of the preparation in Table 1, in Comparative Example 1, the melting point (T _m ) of the prepared polylactide oligomer was as low as 130° C., so it was difficult to remove unreacted lactide. In addition, in the case of Comparative Example 4, it was confirmed that the content of the catalyst within the reaction time was too small, so that polymerization was not sufficiently performed within the reaction time.

In addition, in the product of the first step, the content of unreacted lactide was measured before the second step, and the density and SEM analysis of the polylactide oligomer were performed after the second step. In addition, after the third step of ring-opening polymerization of glycolide at both ends of the polylactide oligomer, the number of dark spots in the block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA) was measured in the following way, and the results are shown in Table 2.

1. Measurement of unreacted lactide content in the product of the first step

¹ H-NMR analysis was performed to analyze the unreacted lactide content, and the analysis conditions are as follows.

- Apparatus: Agilent DD2

- Measuring frequency: 500 MHz

- Temperature: 298 K

- Measuring range: about 8000 Hz

- Delay time: 1.0 sec

-Solvent: Deuterated chloroform (Chloroform-d)

2. Density measurement of polylactide oligomers

The density of the polylactide oligomer was measured by an immersion method according to the ISO 1183-1 density measurement method.

3. Measurement of pore size of polylactide oligomers

In order to measure the pore size of the polylactide oligomer, the polylactide oligomer was cooled with liquid nitrogen, and then the cross section was cut to check the pore size at X30 magnification.

4. Measurement of the number of dark spots in block copolymers of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA)

A specimen having a size of 5 cmX5 cm was prepared using 10 g of the polymer using a press molding machine, and the number of dark spots present in the size was measured.

After the first step, before the second step, polylactide oligomer after step 2
polylactide oligomer Step 3 Preparation of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA) Lactide content (%) density Section pore size number of dark spots Example 1 16.1 0.5794 233㎛~1,107㎛ not observed Example 2 8.7 0.6452 260 μm~797 μm One Comparative Example 1 31.2 - - - Comparative Example 2 2.5 1.2489 43 ㎛~110 ㎛ 5 Comparative Example 3 3.1 1.1035 280 μm~403 μm 6 Comparative Example 4 - - - -

In Table 2, in the case of Comparative Example 1, the content of unreacted lactide was excessive, and the melting point (T _m ) of the prepared polylactide oligomer was low as 130 ° C, making it difficult to remove unreacted lactide. This progress was difficult, and in the case of Comparative Example 4, the content of the catalyst was too small within the reaction time, so that polymerization was not sufficiently performed within the reaction time, so it was difficult to proceed with the analysis.

1 is a diagram illustrating the analysis of polylactide oligomers after the second step of Examples 1, 2, and 2 and Comparative Example 3 with a scanning electron microscope (SEM). 1, the unreacted lactide content in the product after the first step and before the second step was 5 parts by weight or more and 30 parts by weight or less, based on 100 parts by weight of the polylactide oligomer, Example 1 and 2, it was confirmed that pores were formed in the polylactide oligomer.

As a result of Table 2, it was confirmed that the higher the content of unreacted lactide, the lower the density. In addition, it was confirmed from the results of FIG. 1 that the decrease in the density was caused by the formation of pores in the polylactide oligomer.

In addition, when comparing Examples 1, 2 and Comparative Example 2, when the content of the initiator compared to lactide is increased to a certain level, the content of unreacted lactide is lowered to 5% or less. It can be seen that as the concentration of the initiator increases, the number of active sites of the catalyst by the initiator increases and the polymerization degree increases, so that most of the lactide participates in the polymerization reaction and the content of unreacted lactide decreases.

In addition, in comparison with Example 1 and Comparative Example 1, when the reaction temperature is lowered, the polymerization reaction rate is slowed and the unreacted lactide content within the reaction time is increased, but in the product of the first step, unreacted lactide When the amount of tide exceeds 30 parts by weight based on 100 parts by weight of the polylactide oligomer, the melting point of the polylactide oligomer is lowered from 150°C to 160°C to 130°C due to too much unreacted lactide, and unreacted It cannot be used as a material for preparing a block copolymer in the third step because it is difficult to remove at 120° C., which is a condition for removing lactide.

When Example 2, Comparative Examples 3 and 4 were compared, it was confirmed that as the amount of catalyst increased, the polymerization rate within the reaction time increased and the content of unreacted lactide decreased. When the catalyst content is 30 ppm, polymerization was not sufficiently performed within the reaction time, and when the content of the catalyst is 140 ppm, the unreacted lactide content in the product of the first step is 100 ppm of unreacted lactide in the polylactide oligomer. It is less than 5 parts by weight, based on parts by weight, so that the density is increased due to reduction of pores in the polylactide oligomer. As a result, it was confirmed that dark spots were observed due to thermal decomposition of polylactide oligomers having a slower reaction rate and melting rate than glycolide.

Therefore, as a result of Table 2, in the product of the first step, by controlling the content of unreacted lactide, polyglycolide (PGA)-polylactide (PLA)-polyglycol without inhibiting aesthetics and reducing physical properties It was confirmed that a lead (PGA) block copolymer could be prepared.

Claims (5)

a first step of ring-opening polymerization of lactide in the presence of an initiator and a catalyst to prepare a polylactide (PLA) oligomer including hydroxyl groups at both ends;
a second step of adjusting unreacted lactide in the product of the first step to 0 parts by weight or more and 0.5 parts by weight or less, based on 100 parts by weight of the polylactide oligomer; and
a third step of ring-opening polymerization of glycolide at both ends of the polylactide oligomer;
Polyglycolide (PGA)-polylactide, wherein the product in the first step contains 5 parts by weight or more and 30 parts by weight or less of unreacted lactide based on 100 parts by weight of the polylactide oligomer. A method for producing a block copolymer of (PLA)-polyglycolide (PGA). According to claim 1,
In the first step, the amount of the catalyst is 0.005 parts by weight or more and 0.013 parts by weight or less, based on 100 parts by weight of lactide. Polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA) A method for producing a block copolymer of According to claim 1,
The method for preparing a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA), wherein the weight ratio of the lactide and the initiator is 400:1 or more and 600:1 or less. According to claim 1,
The density of the polylactide oligomer is 0.5 g/cm ³ or more and 1 g/cm ³ or less. Preparation of a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA) Way. According to claim 1,
The method for preparing a block copolymer of polyglycolide (PGA)-polylactide (PLA)-polyglycolide (PGA), wherein the molar ratio of the lactide and glycolide is 1:9 or more and 9:1 or less.

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