Polymer manufacturing method

Abstract

To provide a method for readily and efficiently producing highly safe polymers with reduced metal residues.SOLUTION: A method for producing polymers includes following step 1 and step 2. The step 1 is to prepare crude polymers by condensation in a solution. The step 2 is to add α-hydroxycarboxylic acid to a crude polymer-containing solution prepared in the step 1.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing a polymer, and particularly to a method for producing a polymer with a reduced amount of metal residue.

Background Art

[0002] Synthetic polymers with controlled mechanical properties have gained increasing attention in biomedical applications in recent years. However, since metal-based catalysts are frequently used in the synthesis of polymers, metals remain in the synthesized polymers. Such excessive metal residues may cause poisoning, irritation, or inflammation in surrounding tissues in the body, and thus may limit the application of polymers in the field of surgical implants. Tin is a relatively harmless metal and is commonly used in the food packaging industry. Nevertheless, when used together with active pharmaceutical ingredients, it may have undesirable side effects such as promoting drug degradation or may change the drug release profile from pharmaceutical formulations through uncontrolled polymer degradation. Furthermore, metal residues have been reported to cause polymer degradation during the melting process.

[0003] Purification methods for reducing metal residues have already been reported. For example, in Patent Document 1, a method for reducing the tin residue amount by using an extremely low concentration of Sn(Oct)2 in the ring-opening polymerization of lactide and caprolactone is described.

[0004] Also, in Patent Document 2, a purification method for reducing the residual tin content in a tin-containing resorbable polymer to less than 1 ppm by adding an additive such as activated carbon and lactic acid to the washed polymer is described.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

[0006] However, the method described in Patent Document 1 requires a long polymerization time of 10 to 40 days to compensate for the small amount of metal catalyst used. Such a long polymerization time is not economical for industrial production. Furthermore, there was a possibility of uncontrollable polymer molecular weight formation due to decomposition or transesterification.

[0007] Furthermore, the purification method described in Patent Document 2 requires the separate removal of activated carbon from the purified polymer solution. Moreover, the higher the molecular weight of the polymer, the higher the viscosity of the polymer solution, making the removal of activated carbon extremely difficult. For example, when removing activated carbon particles by filtration, the polymer molecular weight is limited to approximately 315k or less.

[0008] The present invention aims to provide a simple and efficient method for producing a highly safe polymer with reduced metal residue levels. [Means for solving the problem]

[0009] As a result of diligent research to solve the above problems, the inventors of this invention have found that metal residues can be efficiently removed from the polymer by adding a specific organic acid to the crude polymer solution immediately after the condensation reaction. The present invention relates to the following polymer manufacturing method. [1] A method for producing a polymer, comprising the following steps 1 and 2. Step 1: A step to obtain a crude polymer by a condensation reaction in a solution. Step 2: Adding α-hydroxycarboxylic acid to the crude polymer-containing solution obtained in Step 1. [2] The method for producing a polymer according to [1], wherein in step 1, the condensation reaction is carried out using a condensing agent and an auxiliary reagent. [3] The method for producing a polymer according to [2], wherein the condensing agent is selected from carbodiimides and the auxiliary reagent is selected from organic bases, organic acids, and complexes thereof. [4] The method for producing a polymer according to [2], wherein in step 2, the condensing agent and the auxiliary reagent are present in the crude polymer-containing solution. [5] A method for producing a polymer according to any one of [1] to [4], wherein the polymer is selected from bioabsorbable polymers and biodegradable polymers. [6] A method for producing a polymer according to any one of [1] to [5], wherein the polymer is selected from polyester and polymers other than polyester linked by ester bonds. [7] The method for producing the polymer according to [6], wherein the polyester is selected from polyglycolic acid, polylactic acid, poly-α-acetolactone, poly-β-propiolactone, poly-γ-butyrolactone, poly-δ-valerolactone, poly-ε-caprolactone, polyhydroxybutyrate, and copolymers thereof. [8] The method for producing a polymer according to [6], wherein the polymer other than polyester linked by ester bonds is a copolymer in which one or more polymers selected from the group consisting of polycarbonate, polyether, polyphosphoester, polyamide, polyurethane, and polyamine are linked by ester bonds. [9] A method for producing the polymer according to any one of [1] to [8], wherein the α-hydroxycarboxylic acid is water-soluble.

[10] A method for producing a polymer according to any one of [1] to [9], wherein the α-hydroxycarboxylic acid is selected from lactic acid and glycolic acid.

[11] A method for producing a polymer according to any one of [1] to

[10] , wherein in step 2, 10% by mass or more of the α-hydroxycarboxylic acid is added relative to the total mass of the crude polymer.

[12] A method for producing a polymer according to any one of [1] to

[11] , wherein in step 2, the α-hydroxycarboxylic acid is stirred in the crude polymer-containing solution for 30 minutes or more.

[13] A method for producing a polymer according to any one of [1] to

[12] , further comprising the following step 3 after step 2. Step 3: Washing the crude polymer solution obtained in Step 2 with water.

[14] A method for producing a polymer according to

[13] , further comprising the following step 4 after step 3. Step 4: Reprecipitation in a poor solvent to obtain a purified polymer. [Effects of the Invention]

[0010] According to the present invention, a highly safe polymer with reduced metal residue can be produced simply and efficiently. In particular, the production method of the present invention carries little risk of reducing the polymer molecular weight and can be carried out quickly and easily. [Modes for carrying out the invention]

[0011] In this specification, "bioabsorbable polymer" refers to a polymer that is biodegradable in living organisms and is metabolized and absorbed within living organisms. Furthermore, a "biodegradable polymer" is a polymer that decomposes into soluble chemical species when corroded by living organisms. Preferably, a biodegradable polymer is a polymer that, under physiological conditions, is nontoxic to living organisms and decomposes into smaller units or chemical species that can be metabolized, excreted, or eliminated by living organisms.

[0012] <Method for producing polymers> The manufacturing method of the present invention comprises the following steps 1 and 2. Step 1: A step to obtain a crude polymer by a condensation reaction in a solution. Step 2: Adding α-hydroxycarboxylic acid to the crude polymer-containing solution obtained in Step 1. The above manufacturing method yields a polymer in which the amount of metal residues such as tin is reduced.

[0013] <Macromonomers> In the production method of the present invention, in the condensation reaction of Step 1, monomers may be reacted with each other, or low molecular weight macromonomers obtained by previously polymerizing monomers may be reacted with each other. From the viewpoint of obtaining a high molecular weight polymer, it is preferable to react macromonomers with each other.

[0014] As the macromonomer, it is preferably selected from a polyester, a copolymer of a polyester and a polymer other than polyester, and a copolymer in which polymers other than polyester are linked by an ester bond. A polymer obtained from such a type of macromonomer is useful as a bioabsorbable polymer or a biodegradable polymer.

[0015] As the polyester, it is preferably selected from polyglycolic acid, polylactic acid, poly-α-acetolactone, poly-β-propiolactone, poly-γ-butyrolactone, poly-δ-valerolactone, poly-ε-caprolactone, polyhydroxybutyrate, and copolymers thereof.

[0016] As the polymer other than polyester, it is preferably selected from polycarbonate, polyether, polyphosphoester, polyamide, polyurethane, and polyamine.

[0017] [[ID=I5]] The synthesis of the macromonomer can be carried out in the presence of a metal catalyst. As the metal catalyst, a catalyst usually used for condensation polymerization or ring-opening polymerization is suitable, a catalyst used for ring-opening polymerization is more suitable, and a catalyst used for ring-opening polymerization of cyclic lactone is even more suitable. Examples of the catalyst include tin catalysts, zinc catalysts, aluminum catalysts, calcium catalysts, lithium catalysts, iron catalysts, etc. From the viewpoints of reaction efficiency and safety after residue, a tin catalyst is preferable. Examples of the tin catalyst include tin(II) 2-ethylhexanoate, tin(II) acetate, tin(IV) acetate, dibutyltin diacetate, dioctyltin(IV) diacetate, tin(II) trifluoromethanesulfonate, tin(II) chloride, etc.

[0018] Macromonomer synthesis may use initiators as needed. The initiator can be selected according to the type of macromonomer, and a compound having one or more hydroxyl groups and one or more carboxylic acid groups is preferred. For example, in the case of polylactic acid, the initiator is preferably lactic acid.

[0019] The monomer ratio in macromonomers can be set appropriately depending on the intended use of the polymer. For example, in the case of a copolymer of lactide and caprolactone, the lactide:caprolactone ratio (molar ratio) can be set in the range of 100:0 to 0:100, preferably 100:0 to 25:75, and more preferably 100:0 to 50:50.

[0020] The polymerization reaction of macromonomers may be carried out using a solvent such as toluene or xylene, or it may be carried out without a solvent.

[0021] From the viewpoint of molecular weight control, the amount of metal catalyst added is preferably 0.001 to 0.004 mol%, and more preferably 0.002 to 0.003 mol%, relative to the monomer.

[0022] The polymerization reaction temperature for macromonomers is preferably 110°C to 145°C, more preferably 120°C to 135°C. The polymerization reaction time for the macromonomer is preferably 5 to 24 hours, more preferably 6 to 9 hours.

[0023] After the polymerization reaction, the resulting macromonomers are dissolved in a good solvent selected from chloroform, dichloromethane, etc., and then precipitated in a poor solvent selected from hexane, cyclohexane, methanol, ethanol, etc., and recovered.

[0024] The weight-average molecular weight (Mw) of the resulting macromonomer is preferably 10k to 200k, and particularly preferably 40k to 100k. A molecular weight within this range is preferable in terms of ease of handling during purification. To achieve a molecular weight within this range, control can be achieved by adjusting the amount of initiator, catalyst, reaction temperature, and reaction time. The weight-average molecular weight is determined by gel permeation chromatography.

[0025] <Step 1: Condensation reaction> The condensation reaction takes place in solution. As the monomer used in the condensation reaction, it is preferable to use the low molecular weight macromonomers mentioned above, since high molecular weight polymers can be easily produced in a single condensation reaction. In other words, the manufacturing method of the present invention preferably includes the following step A before step 1, and it is preferable that step 1 is the following step 1-1. Step A: A step in which monomers are polymerized in the presence of a metal catalyst to obtain macromonomers. Step 1-1: Step to obtain a crude polymer by a condensation reaction of the macromonomers in a solution.

[0026] The solvent used in the condensation reaction is not limited to any solvent that can dissolve monomers or macromonomers, but dichloromethane, chloroform, etc. are preferred, and may be used alone or in combination of two or more.

[0027] In condensation reactions, it is preferable to use a condensing agent and an auxiliary reagent. By using these in combination, the polymer molecular weight can be controlled. The condensing agent has the function of activating carboxylic acids, and is preferably selected from carbodiimides. Specifically, examples include N,N'-diisopropylcarbodiimide (DIC), N,N'-dicyclohexylcarbodiimide (DCC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), which may be used alone or in combination of two or more.

[0028] The auxiliary reagent has a function to assist in proton transfer and is preferably selected from bases or acids. The auxiliary reagent is preferably selected from organic bases, organic acids, and complexes thereof. Specifically, examples include 4-(dimethylamino)pyridinium 4-toluenesulfonate (DPTS), 4-dimethylaminopyridine (DMAP), etc., which may be used alone or in combination of two or more.

[0029] The condensation reaction can be carried out at room temperature. The reaction time is preferably 24 to 72 hours, more preferably 24 to 48 hours.

[0030] Step 1 yields a crude polymer.

[0031] <Step 2: Addition of α-hydroxycarboxylic acid> Next, α-hydroxycarboxylic acid is added to the solution containing the crude polymer obtained in step 1 above. This causes the catalyst-derived metal remaining in the crude polymer to form a chelate with the α-hydroxycarboxylic acid, which can then be easily removed by washing with water. Here, "crude polymer" refers to the polymer immediately after the condensation reaction and before washing with water, etc., and components other than the polymer used in the condensation reaction still exist in the crude polymer-containing solution. When a condensing agent and auxiliary reagents are used in step 1, these reagents remain in the crude polymer solution, and it is presumed that when α-hydroxycarboxylic acid is added to this solution, the remaining reagents promote chelate formation between the metal and the α-hydroxycarboxylic acid. Therefore, it is preferable that the crude polymer solution contains both the condensing agent and auxiliary reagents.

[0032] α-hydroxycarboxylic acids are a type of organic acid that has both a carboxylic acid group and a hydroxyl group on the α-carbon. α-hydroxycarboxylic acids are preferably water-soluble from the viewpoint of being easily removed by washing with water.

[0033] Examples of α-hydroxycarboxylic acids include lactic acid, glycolic acid, glyceric acid, tartaric acid, and malic acid, which may be used individually or in combination of two or more.

[0034] The amount of α-hydroxycarboxylic acid added is preferably 10 to 40% by mass, more preferably 20 to 30% by mass, relative to the mass of the crude polymer. Since α-hydroxycarboxylic acid is an acidic substance, it plays a role in chelating and capturing metals, but if added at high concentrations, there is a concern that the polymer will decompose and the molecular weight will decrease. In the production method of the present invention, since α-hydroxycarboxylic acid can efficiently form chelates with metal residues, metal residues can be sufficiently reduced even at the above low concentrations, and there is no risk of a decrease in polymer molecular weight.

[0035] The crude polymer solution may be diluted with an organic solvent such as dichloromethane to a concentration of 5 to 20% by mass, depending on the polymer molecular weight. This improves the stirability after the addition of α-hydroxycarboxylic acid.

[0036] After adding α-hydroxycarboxylic acid, stir at room temperature. The stirring time is preferably 30 minutes to 24 hours, more preferably 30 minutes to 4 hours, and particularly preferably 2 hours to 4 hours. In the production method of the present invention, α-hydroxycarboxylic acid can efficiently form chelates with metal residues, so the metal residue can be sufficiently reduced with the above short stirring time, and there is no risk of a decrease in polymer molecular weight.

[0037] The above step 2 reduces the amount of metal residue in the crude polymer.

[0038] Furthermore, the weight-average molecular weight of the crude polymer obtained by step 2 is preferably 100k to 1000k, and particularly preferably 150k to 600k. A molecular weight within this range of the crude polymer is preferable in terms of handling and mechanical properties. In addition, the molecular weight of the crude polymer can be controlled by adjusting the amount of condensing agent and auxiliary reagents added. The weight-average molecular weight is determined by gel permeation chromatography.

[0039] <Step 3: Water washing> It is preferable to perform step 3 below after step 2 above. Step 3: Washing the crude polymer solution obtained in Step 2 with water. This removes the α-hydroxycarboxylic acid. The metal residue also migrates to the aqueous layer, forming a chelate with the α-hydroxycarboxylic acid, and is therefore removed along with it. Since the polymer remains in the organic layer, the metal residue and polymer can be separated. Furthermore, the reagents used in the condensation reaction also migrate to the aqueous layer and are removed, similar to the α-hydroxycarboxylic acid.

[0040] As for the specific method of water washing, it is preferable to completely mix the crude polymer solution with an equal or greater amount of water by stirring for a certain period of time, and then remove the aqueous layer. The amount of water used for washing is preferably 1.0 to 1.5 equivalents relative to the crude polymer solution, and the stirring time is preferably 10 to 20 minutes, more preferably 15 to 20 minutes. Water washing may be performed multiple times as needed, preferably three or more times, and more preferably four to five times.

[0041] The purified polymer is obtained through step 3 described above.

[0042] <Step 4: Reprecipitation with a poor solvent> It is preferable to perform step 4 below after step 3 above. Step 4: Reprecipitation in a poor solvent to obtain a purified polymer. This allows for the recovery of solid polymers from polymer solutions and reduces the amount of impurities in the polymers. Examples of poor solvents include hexane, methanol, and ethanol, which may be used individually or in combination of two or more.

[0043] The polymer produced by the above method has a reduced amount of metal residue, preferably 4 ppm by mass to 20 ppm by mass. Furthermore, the amount of metal residue can be quantified using an energy-dispersive X-ray fluorescence elemental analyzer equipped with Quant EZ analysis software. A single-point analysis method is used to determine the amount of metal residue in the form of polymer films prepared by solvent evaporation.

[0044] According to the present invention, a highly safe polymer with reduced metal residue can be produced simply and efficiently. The amount of metal residue can be reduced to 20 ppm by mass or less with just one short stirring step. Furthermore, the production method of the present invention carries little risk of reducing the polymer molecular weight and can be carried out quickly and easily. [Examples]

[0045] The present invention will be further described in detail by the following embodiments, but the scope of the present invention is not limited thereto.

[0046] [Measurement Method 1: Measurement of polymer molecular weight by gel permeation chromatography (GPC)] The polymer was dissolved in chloroform at a concentration of 2 mg / mL and subsequently filtered through a 0.45 μm filter (ADVANTEC DISMIC-13HP). The molecular weight [weight-average molecular weight (Mw) and number-average molecular weight (Mn)] was determined relative to a polystyrene standard. Equipment name: Prominence (manufactured by Shimadzu Corporation) Mobile phase: Chloroform (for HPLC) (manufactured by Wako Pure Chemical Industries, Ltd.) Flow rate: 1mL / min Column: TSKgel GMH HR -M (φ7.8mm x 300mm; manufactured by Tosoh Corporation) Detector: UV (254nm), RI Column and detector temperature: 35°C Standard material: Polystyrene

[0047] [Measurement Method 2: Measurement of residual tin using energy-dispersive X-ray fluorescence (EDXFR)] The amount of Sn residue in the polymer film was determined using a single-point analysis method with an energy-dispersive X-ray fluorescence elemental analyzer equipped with Quant EZ analysis software. The polymer film was prepared by solvent evaporation and cut to specific dimensions with pre-measured area size and weight before being used directly for measurement. Specifically, 10 mL of a polymer solution obtained by dissolving 1 g of polymer in the solvent dichloromethane or chloroform was dropped onto a polytetrafluoroethylene (PTFE) plate, and the solvent was evaporated by natural drying. The resulting film was cut to dimensions of 3.0 mm × 3.0 mm.

[0048] <Example 1> [Synthesis of the low molecular weight macromonomer poly(lactide-co-caprolactone)] The monomers L(-)-lactide (100.0 g, 1.0 molar equivalent, Purac®) and ε-caprolactone (79.2 g, 1.0 molar equivalent, Wako), along with the initiator hydroxypivalic acid (820 mg, 0.01 molar equivalent, TCI), were weighed into separable flasks under N2 conditions. The catalyst, Sn(Oct)2 (562 mg, 0.002 molar equivalent, Wako), was dissolved in a small amount of anhydrous toluene (0.5 mL, Wako), and then added to the same flask under N2 conditions. The reaction mixture was heated to 145°C for 9.0 hours and then cooled to room temperature. The crude polymer was purified by dissolving it in 360 mL of chloroform and then precipitated in 2.5 L of hexane. It was dried overnight in a vacuum oven at 50°C to obtain 157 g of macromonomer product. 1 The monomer ratio determined by 1H-NMR was L(-)-lactide:ε-caprolactone = 51:49. Molecular weights were measured by GPC and found to be Mn(21974), Mw(52739), and Mw / Mn(2.4).

[0049] [Synthesis of high molecular weight polymer poly(lactide-cocaprolactone)] The macromonomer PLA-r-PCL (15.0 g, 1.0 molar equivalent) synthesized above, DPTS (403 mg, 2.0 molar equivalent, synthesized in the laboratory referring to Macromolecules, Vol. 23, No. I, 1990), and DMAP (352 mg, 2.0 molar equivalent, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were weighed into a three-necked round-bottom flask under nitrogen. After completely dissolving in 100 mL of anhydrous dichloromethane, DIC (283 μL, 4.0 molar equivalent, manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the reaction mixture was stirred for 48 hours. A small amount of the crude polymer solution was taken out, precipitated in hexane, and dried in a vacuum oven for GPC analysis. The remaining crude polymer solution was further diluted with 50 mL of dichloromethane and stirred with lactic acid (10% by mass relative to the polymer) for 4.0 hours. The polymer solution was then washed with an equal volume of water for 15 minutes with vigorous stirring, and the upper aqueous layer was discarded. This process was repeated four times. The polymer was recovered by precipitation in 1 L of methanol and dried overnight in a vacuum oven at 50°C to obtain a high molecular weight polymer.

[0050] <Example 2> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-cocaprolactone) was synthesized in the same manner as in Example 1, except that the molar ratio of macromonomer:DIC:DPTS:DMAP was 1:3:2:2, 20% by mass of lactic acid was used, and the stirring time was 3.0 hours.

[0051] <Example 3> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-cocaprolactone) was synthesized in the same manner as in Example 1, except that the molar ratio of macromonomer:DIC:DPTS:DMAP was 1:3:2:2, 30% by mass of lactic acid was used, and the stirring time was 3.5 hours.

[0052] <Example 4> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-cocaprolactone) was synthesized in the same manner as in Example 1, except that 20% by mass of lactic acid was used and the stirring time was 0.5 hours.

[0053] <Example 5> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized in the same manner as in Example 1, except that 30% by mass of lactic acid was used and the stirring time was 0.5 hours.

[0054] <Example 6> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized in the same manner as in Example 2, except that 20% by weight of glycolic acid was used instead of lactic acid. Since glycolic acid is a solid and does not dissolve in organic solvents, it was first dissolved in 10 mL of water and then added to the crude polymer solution.

[0055] <Example 7> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-cocaprolactone) was synthesized in the same manner as in Example 6, except that 40% by weight of glycolic acid was used and the stirring time was 4.0 hours.

[0056] <Comparative Example 1> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized.

[0057] [Synthesis of high molecular weight polymer poly(lactide-cocaprolactone)] The macromonomers PLA-r-PCL (15.0 g, 1.0 molar equivalent), DPTS (403 mg, 2.0 molar equivalent, synthesized in the laboratory), and DMAP (352 mg, 2.0 molar equivalent, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) synthesized above were weighed into the same three-necked round-bottom flask under nitrogen. After completely dissolving in 100 mL of anhydrous dichloromethane, DIC (283 μL, 4.0 molar equivalent, manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the reaction mixture was stirred for 48 hours. The crude polymer solution was further diluted with 50 mL of dichloromethane to adjust the final polymer concentration to 100 mg / mL. The crude polymer solution was then washed with an equal volume of water for 15 minutes with vigorous stirring, and the upper aqueous layer was discarded. This process was repeated four times. The polymer was recovered by precipitation in 1 L of methanol and dried overnight in a vacuum oven at 50°C to obtain 13.4 g of high molecular weight polymer.

[0058] <Comparative Example 2> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. Similar to Comparative Example 1, a high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized.

[0059] [Incubation of high molecular weight polymer poly(lactide-cocaprolactone) with lactic acid] The high molecular weight polymer of poly(lactide-co-caprolactone) synthesized as described above was dissolved in chloroform at a concentration of 100 mg / mL. Then, lactic acid (20% by mass relative to the polymer) was added to the polymer solution and stirred for 4.0 hours. Next, the polymer solution was washed with an equal volume of water for 15 minutes while vigorously stirring, and the upper aqueous layer was discarded. This process was repeated four times. The polymer was recovered by precipitation in methanol at a volume 6 times that of chloroform and dried overnight in a vacuum oven at 50°C.

[0060] <Comparative Example 3> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. Similar to Comparative Example 1, a high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized. The high molecular weight polymer of poly(lactide-cocaprolactone) and lactic acid were stirred in the same manner as in Comparative Example 2, except that 30% by weight of lactic acid was used.

[0061] <Comparative Example 4> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. Similar to Comparative Example 1, a high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized. The high molecular weight polymer of poly(lactide-cocaprolactone) and lactic acid were stirred in the same manner as in Comparative Example 2, except that 40% by weight of lactic acid was used.

[0062] <Comparative Example 5> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. Similar to Comparative Example 1, a high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized. The high molecular weight polymer of poly(lactide-cocaprolactone) and lactic acid were stirred in the same manner as in Comparative Example 2, except that 50% by weight of lactic acid was used.

[0063] <Comparative Example 6> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. Similar to Comparative Example 1, a high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized. The high molecular weight polymer of poly(lactide-cocaprolactone) and lactic acid were stirred in the same manner as in Comparative Example 2, except that 60% by weight of lactic acid was used.

[0064] <Comparative Example 7> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized in the same manner as in Example 2, except that 10% by weight of EDTA was used instead of lactic acid. Since EDTA is a solid and insoluble in organic solvents, it was first dissolved in 10 mL of water and then added to the crude polymer solution. After stirring for 3.0 hours, the polymer solution was washed four more times with water and then precipitated in methanol.

[0065] <Comparative Example 8> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized in the same manner as in Example 2, except that 20% by weight of alanine was used instead of lactic acid and the mixture was stirred for 3.0 hours. Since alanine is a solid and insoluble in organic solvents, it was first dissolved in 10 mL of water and then added to the crude polymer solution. After stirring for 3.0 hours, the polymer solution was washed four more times with water and then precipitated in methanol.

[0066] <Comparative Example 9> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-cocaprolactone) was synthesized in the same manner as in Example 1, except that 20% by weight of acetic acid was used instead of lactic acid and the stirring time was set to 4.0 hours.

[0067] <Comparative Example 10> Similar to Example 1, low molecular weight macromonomers of poly(lactide-co-caprolactone) were synthesized. A high molecular weight polymer of poly(lactide-co-caprolactone) was synthesized in the same manner as in Example 2, except that HCl was used instead of lactic acid. Specifically, the crude polymer solution was washed with an equal volume of HCl (0.5 M) while stirring for 0.5 hours. Then, the aqueous acid layer was removed, and the polymer solution was washed four more times with water, after which it was precipitated in methanol.

[0068] The molecular weight and tin content of the polymers obtained from each of the above examples and comparative examples are shown in the table below.

[0069] [Table 1]

[0070] [Table 2]

[0071] [Table 3]

[0072] Based on the above results, in the production methods of Examples 1 to 6, in which lactic acid or glycolic acid was added to the crude polymer solution, the residual tin content was reduced to 20 ppm by mass or less. Furthermore, there was almost no decrease in polymer molecular weight before and after the addition of lactic acid or glycolic acid. In the manufacturing method of Comparative Example 1, which did not involve the addition of acid, and in the manufacturing methods of Comparative Examples 2-6, in which lactic acid was added to the polymer solution after water washing rather than to the crude polymer solution, a high concentration of residual tin was observed. Furthermore, the polymer molecular weight decreased before and after the addition of acid. The manufacturing methods for Comparative Examples 7 to 10, in which acids other than α-hydroxycarboxylic acid were added, also showed high concentrations of residual tin, similar to Comparative Example 2. [Industrial applicability]

[0073] According to the present invention, highly safe, high-molecular-weight polymers with reduced metal residue levels can be produced simply and efficiently. Polymers with low metal residue levels are suitable for various biomedical applications, such as bioreabsorbable polymers and biodegradable polymers. In tissue engineering, these polymers are often used in conjunction with hydrogels to construct 3D scaffolds for cell regeneration and differentiation. These polymers are suitable materials for medical implant devices and drug delivery systems (DDS). Beyond biomedical applications, biodegradable polymers also find various uses in agriculture, veterinary medicine, food processing, and packaging.

Claims

1. The process comprises the following steps 1 and 2: Step 1: A process to obtain a crude polymer by a condensation reaction in solution in the presence of a tin catalyst. Step 2: Adding α-hydroxycarboxylic acid to the crude polymer-containing solution obtained in Step 1. In step 1, the condensation reaction is carried out using a condensing agent and an auxiliary reagent. The coupling agent is selected from carbodiimides, and the auxiliary reagents are selected from organic bases, organic acids, and complexes thereof. A method for producing a polymer, wherein in step 2, the condensing agent and the auxiliary reagent are present in the crude polymer-containing solution, A method for producing a polymer, wherein the polymer is a polyester selected from polyglycolic acid, polylactic acid, poly-α-acetolactone, poly-β-propiolactone, poly-γ-butyrolactone, poly-δ-valerolactone, poly-ε-caprolactone, polyhydroxybutyrate, and copolymers thereof.

2. The method for producing a polymer according to claim 1, wherein the polymer is selected from bioabsorbable polymers and biodegradable polymers.

3. A method for producing a polymer according to claim 1 or 2, wherein the α-hydroxycarboxylic acid is water-soluble.

4. A method for producing a polymer according to any one of claims 1 to 3, wherein the α-hydroxycarboxylic acid is selected from lactic acid and glycolic acid.

5. A method for producing a polymer according to any one of claims 1 to 4, wherein in step 2, 10% by mass or more of the α-hydroxycarboxylic acid is added relative to the total mass of the crude polymer.

6. A method for producing a polymer according to any one of claims 1 to 5, wherein in step 2, the α-hydroxycarboxylic acid is stirred in the crude polymer-containing solution for 30 minutes or more.

7. A method for producing a polymer according to any one of claims 1 to 6, further comprising the following step 3 after step 2. Step 3: Washing the crude polymer solution obtained in Step 2 with water.

8. A method for producing a polymer according to claim 7, further comprising the following step 4 after step 3. Step 4: Reprecipitation in a poor solvent to obtain a purified polymer.

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