KR20190053168A - Method for purifying biodegradable polymers - Google Patents

Abstract

The present invention relates to a method for purifying a biodegradable polymer, which is to obtain ultra-high purity polymers, comprising the steps of: extracting a residual monomer from a polymer; and removing the monomer extracted from the polymer.

Description

[0001] The present invention relates to a method for purifying biodegradable polymers,

The present invention relates to a process for simply and efficiently removing an unreacted monomer remaining in a polymer in the course of producing a biodegradable polymer such as a polylactic acid or a derivative thereof to obtain an ultrahigh-purity polymer, and more particularly, , The solid biodegradable polymer is contacted with an organic solvent containing a secondary or tertiary alcohol to remove only the residual monomer from the solid polymer by solid-liquid extraction, thereby to obtain an ultra-high-purity biodegradable polymer As well as a method for obtaining the same.

(PDLA), poly-D, L-lactic acid (PDLLA), poly (L-lactide-co-D, L-lactide) (PLDLLA ), Polylactic acid and its derivatives including polylauric acid (PGA), L-lactic acid-glycolic acid copolymer (PLLGA), D, L-lactic acid-glycolic acid copolymer (PDLLGA) Biodegradable polymers have been widely used in various fields such as drug delivery and medical devices due to their biocompatibility and their decomposition into lactic acid or glycolic acid that is harmless to the human body.

Among these biodegradable polymers, in particular, biodegradable polymers for medical use, synthetic polymers that have been most actively studied and used are polyesters based on alpha-hydroxy acid, and among them, lactic acid and / Or glycolic acid as constituent units are most well known. These polymers are generally synthesized by ring-opening polymerization of glycolide or lactide, which is a cyclic dimer obtained by decompressing the oligomer produced by heating dehydration condensation of monomers and heating and decomposing the monomer. As the catalyst for polymerization, an ester compound of divalent tin such as Tin-2-ethylhexanoate is used, and an alcohol such as lauryl alcohol is used as an initiator. The polymer block thus obtained is then subjected to an additional process such as cutting, grinding or pelletizing to form a polymer chip or pellet.

The unreacted monomers remaining in the polymer obtained by the above polymerization process are then hydrolyzed rapidly, and the hydrolysis products of these monomers accelerate the decomposition of the polymer. (Tg) and melting point (Tm) of the polymer due to the addition of the monomer resulting from the hydrolysis of the monomer to the polymer, thereby changing the physical properties of the polymer depending on the content of the residual monomer . Therefore, in order to stably maintain the physical properties of the polymer, it is necessary to remove the remaining unreacted monomer. Generally, the residual monomer is removed by a method of applying heat and vacuum drying, and the content of the residual monomer finally contained in the polymer is preferably 0.5 wt% or less. However, when the monomer is removed by the reduced pressure drying method During the process, the addition of heat causes the hydrolysis of the monomer due to a small amount of water in the polymer, which leads to the decomposition of the polymer, and the change in physical properties of the polymer after drying may be observed.

US Pat. No. 5,3190,388 A discloses a solid-liquid extraction method using acetone to remove residual monomer from high molecular weight PLLA, and describes the removal of monomer without changing the physical properties of the polymer. However, this method is applied only to polymers such as PLLA having high crystallinity of high molecular weight, and amorphous polymers such as PDLLA, PLDLLA and PLGA are not applicable because they are dissolved in acetone.

Korean Patent No. 10-1119861 discloses a method in which a polymer is dissolved in an organic solvent, an alkali metal salt aqueous solution is added thereto, the monomer is removed by liquid-liquid extraction to remove the polymer, and the organic layer containing the polymer is precipitated again, And how to get it. However, this method has the disadvantage that it is necessary to remove the monomer after once dissolving the polymer, and then to re-precipitate the polymer.

The object of the present invention is to dissolve not only PLLA which is a crystalline biodegradable polymer but also unreacted monomers contained in a polymer in an organic solvent without dissolving polymers such as PDLLA, PLDLLA and PLLGA having amorphous characteristics, - removing the residual monomer through a liquid extraction method and obtaining a biodegradable polymer of ultra high purity.

According to an aspect of the present invention, there is provided a method for producing a biodegradable polymer, comprising the steps of: (1) contacting a biodegradable polymer in a solid state with a secondary alcohol, a tertiary alcohol or a mixture thereof to extract a residual monomer from the polymer by a solid- And (2) removing the monomer extracted from the polymer. The present invention also provides a method for purifying a biodegradable polymer.

According to another aspect of the present invention, there is provided a biodegradable polymer purified or prepared according to the above method, wherein the content of the residual monomer measured by ¹ H NMR is 0.5% (w / w) or less.

According to the present invention, an unreacted monomer remaining in a polymer can be removed simply and efficiently, without deteriorating the physical properties of the polymer, to produce an ultra-high-purity crystalline or amorphous biodegradable polymer (for example, polylactic acid or its derivative) .

Figure 1 shows the hydrogen nuclear magnetic resonance spectra ( ¹ ) before (top) and after (bottom) treatment of poly (D, L-lactide) (PDLLA) with isopropanol (IPA) H NMR).

Hereinafter, the present invention will be described in more detail.

In the present invention, the term " biodegradable polymer " means a polymer having excellent biocompatibility and decomposing into a harmless component such as lactic acid or glycolic acid.

In one embodiment, the biodegradable polymer is an aliphatic polyester having alpha-hydroxyl acid units, and may be composed of lactic acid and / or glycolic acid. It may be in units.

In one embodiment, the biodegradable polymer may be a polyglycolic acid (PGA), a polylactic acid (PLA), or a lactic acid-glycolic acid copolymer (PLGA).

In one embodiment, the biodegradable polymer may be a polylactic acid or a polylactic acid derivative.

In one embodiment, the polylactic acid derivative is selected from, for example, polyglycolide, polymandelic acid, polycaprolactone, polydioxan-2-one polyamino acid, polyorthoesters, polyanhydrides, And copolymers thereof. More specifically, the polylactic acid derivative is polylactide, polyglycolide, polycaprolactone, or polydioxan-2-one.

In one embodiment, the biodegradable polymer is selected from the group consisting of poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-D, L-lactic acid (PDLLA) -D, L-lactide) (PLDLLA), polyglycolic acid (PGA), L-lactic acid-glycolic acid copolymer (PLLGA) and D, L-lactic acid-glycolic acid copolymer May be one or more selected from the group.

In one embodiment, the biodegradable polymer is selected from the group consisting of polylactic acid, a copolymer of lactic acid and glycolic acid, a copolymer of lactic acid and caprolactone, and a copolymer of lactic acid and 1,4-dioxan-2-one Lt; / RTI >

The term " polylactic acid " or " polylactic acid derivative " is a concept collectively referred to as polylactic acid and polylactic acid derivative, unless the context clearly indicates otherwise. There is no difference in purification method between the titanic acid derivatives.

In one embodiment, the number average molecular weight of the biodegradable polymer may be, but is not limited to, 1,000 to 500,000 daltons, more specifically 10,000 to 300,000 daltons. The purification method according to the present invention is applicable not only to a biodegradable polymer having a low molecular weight (for example, polylactic acid or a derivative thereof) but also to a biodegradable polymer having a high molecular weight.

In the present invention, the biodegradable polymer in a solid state is contacted with a secondary or tertiary alcohol or a mixture thereof to remove the residual monomer from the polymer by a solid-liquid extraction method.

In the present invention, amorphous polymers such as PLLA, PLDLLA, and PLLGA as well as crystalline polymers such as PLLA, and polymers having a low molecular weight and high molecular weight, The residual monomers are removed through a solid-liquid extraction process.

Amorphous polymers tend to be soluble in most aprotic solvents because of their weak resistance to organic solvents. Therefore, alcohols which are protic solvents are considered as the solvent which does not dissolve the amorphous polymer. However, when the unreacted monomer remains in the polymer and is exposed to the alcohol, the ring-opening of the cyclic monomer by the hydroxyl group of the alcohol occurs, and the resultant product accelerates the decomposition of the polymer. This is due to the same mechanism as the above-mentioned moisture causes degradation of the physical properties of the polymer.

Therefore, in the present invention, in order to suppress the decomposition of the polymer caused by the hydrolysis of the monomer during the monomer elimination process, a secondary alcohol (an alcohol compound in which the hydroxyl group is attached to the secondary carbon), which is difficult to react with the residual monomer, A tertiary alcohol (an alcohol compound in which a hydroxy group is attached to a tertiary carbon), or a mixture thereof. The secondary and tertiary alcohols can inhibit the decomposition of the polymer during the monomer removal process because it is difficult to cause the ring opening reaction of the lactide monomer by the steric hindrance effect as compared with the primary alcohol do.

In one embodiment, the secondary or tertiary alcohols can be straight chain or branched aliphatic secondary or tertiary alcohols having 3 or more carbon atoms (e.g., 3 to 10, or 3 to 6, or 3 to 5) .

In one embodiment, the secondary alcohol may be one or more selected from the group consisting of isopropanol (IPA, also referred to as isopropyl alcohol), 2-butanol and 3-pentanol, and more specifically may be isopropanol.

In one embodiment, the tertiary alcohol may be at least one selected from the group consisting of tert-butanol and tert-amyl alcohol, and more specifically tert-butanol.

The solid-liquid extraction method used in the present invention is a solid-liquid extraction method in which an object to be treated (that is, a solid biodegradable polymer) is dissolved in an extraction solvent for dissolving an impurity component (i.e., residual monomer) (I.e., secondary or tertiary alcohols) are mixed and contacted with each other, and then the impurities are removed from the solid by treating only the solid components while leaving the impurity components in the extraction solvent through filtration.

In one embodiment, the mixing ratio of the secondary or tertiary alcohol: biodegradable polymer may be from 1: 1 to 1: 100 (w / v), more specifically from 1: 2 to 1:10 (w / v).

In one embodiment, the time for extracting the unreacted monomers remaining in the biodegradable polymer with a secondary or tertiary alcohol may be from 0.5 to 24 hours, and more specifically from 4 to 12 hours.

In one embodiment, the temperature at which the unreacted monomer remaining in the biodegradable polymer is extracted with a secondary or tertiary alcohol may be 0 to 90 ° C, more specifically 25 to 60 ° C.

In one embodiment, the step of extracting the unreacted monomers remaining in the biodegradable polymer with a secondary or tertiary alcohol may be repeated one time or more and less than 20 times, more specifically, two to five times Can be repeatedly carried out. After each washing, the polymer is filtered to separate the polymer from the extraction solvent. The solid polymer chip or pellet obtained after filtration is vacuum-dried in an oven to remove the residual solvent. The temperature of the oven during the reduced-pressure drying may be 20 to 120 ° C, more specifically 40 to 90 ° C. The drying time may be 1 day or more, more specifically 2 to 10 days.

Accordingly, the method and the method for purifying a biodegradable polymer according to the present invention further include a step of recovering the solid polymer by filtering the resultant mixture obtained after performing the solid-liquid extraction method, and drying the recovered polymer under reduced pressure can do.

When the biodegradable polymer is purified or prepared according to the present invention, an ultra-high-purity biodegradable polymer having no residual monomer (i.e., residual monomer content ND (Not detected)) measured by 1H NMR can be obtained. Accordingly, according to another aspect of the present invention, there is provided a biodegradable polymer which is purified or prepared according to the purification method or the production method of the present invention, and has a residual monomer as measured by ¹ H NMR of not more than 0.5% (w / w) Is provided.

Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

In order to confirm the effectiveness of the monomer removal by vacuum drying and the monomer removal method by the solid-liquid extraction method using the primary alcohol, the following Comparative Examples 1 to 4 were carried out.

Comparative Example 1: Removal of residual monomer from PLLA by vacuum drying

1 kg of PLLA was placed in a stainless steel tray and the tray was placed in the oven. The temperature of the oven was set at 20 DEG C, and vacuum drying was performed for about 1 hour. Then, the temperature of the oven was raised to 40 DEG C, dried for 4 to 12 hours, finally heated to 90 DEG C, and dried for 10 days. The samples thus removed from the monomer by the reduced pressure drying were taken out of the oven and subjected to ¹ H NMR and IV (inherent viscosity) measurement. IV measurements were carried out in a chloroform (CHCl ₃ ) solvent at 25 ° C and c = 0.1 g / dL using a Ubelohde viscosity tube. ^The changes in the residual monomer content by ¹ H NMR measurement and the results of IV measurement are shown in Table 1 below.

Comparative Example 2: Removal of residual monomer from PDLLA by vacuum drying

1 kg of PDLLA was placed in a stainless steel tray and the tray was placed in the oven. The temperature of the oven was set at 20 DEG C, and vacuum drying was performed for about 1 hour. The temperature of the oven was then raised to 40 DEG C, dried for 4 to 12 hours, finally heated to 80 DEG C and dried for 10 days. The sample thus removed from the oven by the reduced pressure drying was subjected to ¹ H NMR and IV measurements. ^The changes in the residual monomer content by ¹ H NMR measurement and the results of IV measurement are shown in Table 1 below.

Comparative Example 3: Removal of residual monomer from PLLA using methanol

10 g of the PLLA chip was placed in a flask, and 20 ml of anhydrous methanol was added thereto. The thus obtained mixed solution was stirred or left at room temperature for about 4 hours. The methanol was then discarded and replaced with fresh methanol. This process was carried out four times in total, and then the methanol was discarded through filtration, and the obtained PLLA chip was dried in an oven. The drying temperature was 40 占 폚 and the drying time was 4 to 12 hours. After methanol drying was completed, the sample was taken out of the oven and subjected to ¹ H NMR and IV measurements. ^The changes in the residual monomer content by ¹ H NMR measurement and the results of IV measurement are shown in Table 1 below.

Comparative Example 4: Removal of residual monomer from PDLLA using ethanol

10 g of PDLLA chip was placed in a flask, and 20 ml of anhydrous ethanol was added thereto. The thus obtained mixed solution was stirred or left at room temperature for about 4 hours. The ethanol was then discarded and replaced with fresh ethanol. This process was carried out four times in total, and then all of the ethanol was filtered out, and the obtained PDLLA chip was dried in an oven. The drying temperature was 40 占 폚 and the drying time was 4 to 12 hours. After the ethanol drying was completed, the sample was taken out of the oven and subjected to ¹ H NMR and IV measurements. ^The changes in the residual monomer content by ¹ H NMR measurement and the results of IV measurement are shown in Table 1 below.

[Table 1] Results obtained from experiments of Comparative Examples 1 to 4

As shown in Table 1, in the case of the PLLA sample (Comparative Example 1) in which the monomer was removed by reduced-pressure drying, the monomer remained after the reduced-pressure drying. It was also observed that IV was decreased by 15% as compared with before drying. In Comparative Example 2, similar results were obtained. That is, the monomer still remained after the reduced pressure drying and a decrease in IV was observed.

It is noteworthy that in Comparative Example 3 in which monomer removal was attempted by the solid-liquid extraction method using methanol, the IV was reduced after treatment with methanol. A decrease in IV was similarly observed in the case of Comparative Example 4 in which the solid-liquid extraction method using ethanol was used. This is presumably due to the ring-opening reaction of the monomer with the primary alcohol and subsequent decomposition of the polymer.

Next, monomer removal experiments using secondary or tertiary alcohols were conducted as in Example 1, Example 2, and Example 3 below.

Example  1: Using isopropanol PLDLLA  Removal of residual monomer from 70/30

10 g of PLDLLA 70/30 (L-lactide: D, L-lactide molar ratio = 70: 30) was taken in a flask and 100 ml of isopropyl alcohol was added thereto. The internal temperature at the time of stirring was set at 60 캜. After stirring for about 1 to 4 hours, the isopropanol was removed by filtration and replaced with the same amount of fresh isopropanol. This process was performed four times in total. Finally, the PLDLLA 70/30 chip obtained through filtration was dried under reduced pressure to remove the residual solvent. The temperature of the oven set to remove isopropanol was 40-80 ° C. After isopropanol drying was completed, the sample was taken out of the oven and subjected to ¹ H NMR and IV measurements. ^The results of the measurement of the residual monomer content and IV by ¹ H NMR measurement are shown in Table 2 below.

Example 2 Removal of Residual Monomers from PDLLA Using tert-Butanol

10 g of PDLLA was taken in a flask, and 100 ml of tert-butanol was added thereto and stirred. The internal temperature at the time of stirring was set at 40 占 폚. After stirring for about 1 to 4 hours, tert-butanol was removed by filtration and replaced with the same amount of fresh tert-butanol. This process was performed four times in total. Finally, the PDLLA chip obtained through filtration was dried under reduced pressure to remove the residual solvent. The temperature of the oven set to remove tert-butanol was 40-80 ° C. After the tert-butanol drying was completed, the sample was removed from the oven and subjected to ¹ H NMR and IV measurements. ^The results of the measurement of the residual monomer content and IV by ¹ H NMR measurement are shown in Table 2 below.

Example 3 Removal of Residual Monomers from PDLLA Using Isopropanol

10 g of PDLLA was taken in a flask, and 100 ml of isopropanol was added thereto and stirred. The internal temperature at the time of stirring was set at 50 캜. After stirring for about 1 to 4 hours, the isopropanol was removed by filtration and replaced with the same amount of fresh isopropanol. This process was performed four times in total. Finally, the PDLLA chip obtained through filtration was dried under reduced pressure to remove the residual solvent. The temperature of the oven set to remove isopropanol was 40-80 ° C. After isopropanol drying was completed, the sample was taken out of the oven and subjected to ¹ H NMR and IV measurements. ^The results of the measurement of the residual monomer content and IV by ¹ H NMR measurement are shown in Table 2 below. In addition, ¹ H NMR charts before and after monomer removal are shown in FIG.

[Table 2] Results obtained from the experiments of Examples 1 to 3

As shown in Table 2, when the monomer removal by the solid-liquid extraction method using the secondary or tertiary alcohols was attempted as in Examples 1 to 3, no decrease in properties such as IV reduction was observed at all . In particular, it was confirmed that when the extraction was carried out by heating to 60 ° C using IPA as in Example 1, the residual monomer could be completely removed. It was confirmed that the solid - liquid extraction type monomer removal method using secondary or tertiary alcohols is effective.

Claims (1)

(1) contacting a solid biodegradable polymer with a secondary alcohol, a tertiary alcohol or a mixture thereof to extract a residual monomer from the polymer by a solid-liquid extraction method; And
(2) removing the monomer extracted from the polymer,
Wherein the secondary alcohol or tertiary alcohol is isopropanol or tert-butanol,
Wherein the biodegradable polymer is poly-D, L-lactic acid (PDLLA) or poly (L-lactide-co-D, L-lactide)
A method for purifying a biodegradable polymer.

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