JPH0610252B2 - Polymer manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a polymer of lactic acid or glycolic acid or a copolymer thereof (hereinafter collectively referred to as polylactic acids).

In recent years, degradable polymers have attracted considerable attention as easily degradable polymers for mitigating plastic pollution and as polymers for bioabsorbable pharmaceutical preparations.

As a purpose for the above purposes, JP-A-56-45920 discloses a method of polymerizing lactic acid and glycolic acid in the presence of a strongly acidic ion exchange resin, according to which, It is said that a polymer having an average molecular weight of about 6,000 to 35,000 and containing substantially no polymerization catalyst can be obtained.

However, the polymer produced by the above method has a large molecular weight dispersity of about 3 or more, and when it acts,
Since factors such as solubility and other aspects are complicated and there are many problems in control, it is not preferable when used as a polymer for bioabsorbable pharmaceutical preparations. Moreover, in this method, the strongly acidic ion-exchange resin used as the polymerization catalyst is deteriorated by heat during the heat polycondensation reaction and is dissolved in the obtained polymer, which appears as coloring of the polymer. Furthermore, it is difficult to remove such color from once colored polymers and practically impossible to completely remove it. It goes without saying that such coloring not only reduces the commercial value but is also in an unfavorable state because it is caused by impurities.

In view of such a situation, the inventors of the present invention have conducted earnest studies on a production method of polylactic acid which is effective and does not have the above-mentioned drawbacks, and as a result, lactic acid and / or glycolic acid was added in the presence of an inorganic solid acid catalyst. A colorless or almost white polylactic acid having a large weight-average molecular weight of about 5,000 or more and a low polydispersity of about 1.5 to 2 by the condensation reaction and containing no or substantially no polymerization catalyst. The present invention has been completed as a result of the discovery that a class of compounds can be obtained and further research based on this.

The present invention is characterized by using an inorganic solid acid catalyst as a catalyst when polycondensing lactic acid and / or glycolic acid to produce a polymer, and polymer of lactic acid or glycolic acid or copolymers thereof. It is a manufacturing method of coalescence.

In the method for producing polylactic acid of the present invention, an aqueous lactic acid solution having various concentrations is usually arbitrarily selected as the lactic acid used as a raw material, but from the viewpoint of workability, the higher the lactic acid concentration, the better.
% Or more is desirable. Needless to say, it is better to use lactic acid itself rather than the aqueous solution if available. As the glycolic acid, crystalline one is usually used as it is, but it may be used as an aqueous solution. When solid lactic acid and glycolic acid such as crystals are used, a solvent that dissolves them may be used if necessary. Examples of the solvent include water, methanol, ethanol, acetone and the like.

In the method for producing polylactic acid of the present invention, as lactic acid and / or glycolic acid used as a raw material, a low molecular weight polymer thereof may be used, or in the case of obtaining a copolymer, a low molecular weight polymer thereof may be used. A molecular copolymer may be used.

Examples of the low molecular weight polymer include lactic acid oligomers (eg, dimers, trimers, etc.), glycolic acid oligomers (eg, dimers, trimers, etc.), and the like.

Further, examples of the low molecular weight polymer or the low molecular weight polymer include those obtained by polycondensing lactic acid and / or glycolic acid in the absence of a catalyst. The reaction temperature and reaction time for producing the low molecular weight polymer or low molecular weight copolymer are, for example, 100 to 150 ° C./350 mmHg for 2 hours or more, usually about 2 to 10 hours, for example, 105 ° C. / 350mmHg to 150 ℃
/ 30mmHg while gradually increasing the temperature and decompression degree
Moisture may be removed by heating and reacting under reduced pressure for 6 hours. In this way, a low molecular weight polymer having a molecular weight of about 2000 to 4000 or a low molecular weight polymer can be easily obtained.

Further, the low molecular weight polymer or the low molecular weight polymer may be obtained by polycondensation by a known method without catalyst. Examples of the known method include, for example, Industrial Chemistry Magazine Vol. 68, 98.
The method described on pages 3 to 986 (1965), that is, the method of reacting lactic acid and glycolic acid at 202 ° C. for 6 hours at atmospheric pressure without a catalyst can be mentioned. As the known method, for example, the method described in US Pat. No. 2,362,511, that is, lactic acid and glycolic acid are reacted at a temperature of 200 ° C. for 2 hours,
Then, a method of continuing heating under reduced pressure for 1/2 hour may be used.

The polylactic acid according to the present invention is a polymer of lactic acid containing only lactic acid or a polymer of glycolic acid containing only glycolic acid, or any ratio of lactic acid to glycolic acid, preferably about lactic acid.
50-95% by weight and about 50-5% by weight glycolic acid, more preferably about 60-95% by weight lactic acid and about 40-5% by weight glycolic acid, even more preferably about 60-85% by weight lactic acid and about 40-% glycolic acid. It consists of a copolymer of 15% by weight of lactic acid and glycolic acid. Particularly preferred ratios in the copolymer of lactic acid and glycolic acid include about 75 ± 2 mol% lactic acid and about 25 ± 2 mol% glycolic acid.

Examples of the inorganic solid acid catalyst used in the present invention include acidic clay, activated clay, bentonite, kaolin, talc, aluminum silicate, magnesium silicate, alumina bolilla, silicic acid and the like. These may be used either individually or as a mixture of two or more thereof, and either of them may be used as they are or, if necessary, for removing metal ions, for example, about 5 to 20.
It is used after being washed with hydrochloric acid having a concentration of%.

The amount of the inorganic solid acid catalyst used in the present invention is usually about 0.5 to 30% W based on the total amount of lactic acid and / or glycolic acid.
/ W, preferably about 1 to 20% W / W is used once or several times in a divided manner. The catalyst may be added to the reaction system during the reaction.

The reaction temperature in the polycondensation reaction of the present invention is, for example, usually about
The temperature is 150 to 250 ° C, preferably about 150 to 200 ° C. This reaction is preferably carried out under reduced pressure, and the reduced pressure is, for example, usually about 30 to 1 mmHg, preferably about 10 to 1 mmHg. The reaction time of this reaction is, for example, usually about 10 hours or longer, preferably about 10 to 150 hours, more preferably about 10 to 1 hours.
It's 00 hours.

The following reaction conditions are preferable when lactic acid and / or glycolic acid is used as the raw material. For example,
100-150 ℃ / 350-30mmHg for 2 hours or more, usually 2-1
About 0 hours, for example, 105 ℃ / 350mmHg to 150 ℃ / 30mm
After removing water by heating reaction under reduced pressure for 5 to 6 hours while gradually increasing temperature and reduced pressure to Hg, 15
The dehydration polycondensation reaction is performed at 0 to 200 ° C / 10 to 1 mmHg for 10 hours or more (usually about 100 hours).

The following reaction conditions are preferable when the above-mentioned low molecular weight polymer or copolymer is used as a raw material. That is, for example, at 150-200 ℃ / 10-1mmHg
Allow dehydration polycondensation reaction for 10 hours or more (usually about 100 hours).

After completion of the reaction, the reaction solution is simply heated, or the polymer is dissolved in an appropriate solvent such as methylene chloride, dichloroethane, chloroform, or acetone (the same amount to about 10 times as much as the polymer is used). By removing the solid acid catalyst used (the solid acid catalyst method of the present invention can be easily removed by suction suction using ordinary qualitative paper, etc.). By itself, and in the latter case, that is, when the reaction solution is dissolved in a solvent and passed over, the target high molecular weight polylactic acid can be easily obtained by concentrating and distilling off the solvent used. If necessary, the excess reaction solution may be separated directly, or in the case of using a solvent, a concentrated solution may be separated by a conventional method such as pouring into a large amount of a precipitant, or if necessary, further. It may be purified by reprecipitation or the like. When the ion exchange resin and the catalyst are used, the coloring cannot be easily removed even by repeating such operations.

According to the present invention, a high molecular weight polylactic acid having a weight average molecular weight of about 5,000 or more (preferably about 5,000 to 30,000) can be obtained, and the obtained polymer has a small dispersity of about 1.5 to 2 and an appearance. Almost no coloring was observed, and no or substantially no polymerization catalyst was contained.

According to the present invention, the production can be easily carried out industrially. Further, since the polymerization catalyst used is neither soluble in polylactic acid nor in a solvent, it can be completely removed from the product. Therefore, it is possible to easily obtain a high molecular weight polymer having a dispersion degree of about 1.5 to 2 with substantially no mixing of the polymerization catalyst into the obtained polymer and almost no coloring of the polymer. .

In the method of the present invention, since an inorganic solid acid catalyst is used, there is an advantage that the reaction time can be shortened as compared with the case where this is carried out without a catalyst. That is, according to the method of the present invention, a polymer or copolymer having the same molecular weight can be obtained with a reaction time shorter than that in the case of carrying out without a catalyst.

The polymer or copolymer of the present invention can be mainly used as a drug formulation base. For example, steroid hormones, peptide hormones, or carcinostatic agents, etc. are contained, and they can be advantageously used as implantable or microcapsule sustained-release preparations, or fine particles containing carcinostatic agents are prepared and embolization therapeutic agents.

Hereinafter, the present invention will be described in more detail with reference to experimental examples and examples.

Experimental example 1. (Lactic acid homopolymerization) 6.8g of inorganic solid acid catalyst was added to 160g of 85% lactic acid aqueous solution (1.5mol of lactic acid), and 100-150 ℃ / 350 under nitrogen stream.
Distilled water was removed by heating under reduced pressure stepwise at -30 mmHg for 6 hours. After that, 6.8g of solid acid catalyst was added and 175 ℃
The dehydration polycondensation reaction was carried out at / 6 to 5 mmHg for 72 hours.

Table 1 shows the relationship between the reaction time and the reached weight average molecular weight in the production of lactic acid polymer by this method.

In addition, for comparison, the results obtained when a commercially available strong acid ion exchange resin, Dowex 50W [Dow Chemical Company (USA), registered trademark] is used as a polymerization catalyst are also shown in Table 1.
Shown in.

In the present specification, the weight average molecular weight and the dispersity (dispersion degree = weight average molecular weight / number average molecular weight) are determined by gel permeation chromatography using standard polystyrene having a known molecular weight.

In the table, the catalyst addition amount (1) represents the initial catalyst addition amount, and the catalyst addition amount (2) represents the catalyst addition amount added at the start of the polycondensation reaction of 175 ° C./6 to 5 mmHg after removal of water. Time is 17
It represents that at 5 ° C / 6-5 mmHg. The value in parentheses below the reached molecular weight in the table represents the degree of dispersion.

As is apparent from Table 1, according to the present invention, it is possible to easily obtain a high molecular weight polylactic acid having a weight average molecular weight of about 5,000 or more, in which a polymerization catalyst is hardly dissolved, and almost no polymer is obtained. No coloration was observed, and the molecular weight and acidity were all as small as 2 or less, and the reaction rate of the polymerization reaction was obviously accelerated by the addition of the catalyst.

Experimental example 2. (Lactic acid / glycolic acid copolymerization) 85% lactic acid aqueous solution 160g (1.5mol) and glycolic acid 38g (0.5m
ol), and 8.7 g of an inorganic solid acid catalyst was added thereto, and the mixture was heated under reduced pressure at 100 to 150 ° C./350 to 30 mmHg for 6 hours under a nitrogen stream to remove distilled water. Then further solid acid catalyst
An additional 8.7 g was added and a dehydration condensation reaction was carried out at 175 ° C./6-5 mmHg for 72 hours.

Table 2 shows the relationship between the reaction time, the reaching time and the reaching weight average molecular weight in the production of the lactic acid-glycolic acid copolymer by this method.

For comparison, Table 2 also shows the results when a strongly acidic ion exchange resin (Dowex 50W) was used as the polymerization catalyst.

In Table 2, the catalyst addition amount (1) represents the initial catalyst addition amount, and the catalyst addition amount (2) represents the catalyst addition amount added at the start of the polycondensation reaction at 175 ° C./6 to 5 mmHg after the removal of water. The reaction time represents that at 175 ° C./6-5 mmHg. The value in parentheses below the reached molecular weight in the table represents the degree of dispersion.

As is apparent from Table 2, according to the present invention, a high-molecular-weight lactic acid / glycolic acid copolymer having a weight average molecular weight of about 5,000 or more and having almost no dissolved polymerization catalyst can be easily obtained. Almost no coloration was observed in the copolymer, and a polymer having a small molecular weight acidity of 2 or less was obtained. Also,
The reaction rate of the polymerization reaction was also obviously accelerated by the addition of the catalyst.

Table 3 shows the results of analyzing the copolymerization composition of lactic acid and glycolic acid by nuclear magnetic resonance spectroscopy using the above-mentioned copolymer of the present invention as a deuterated chloroform solution.

Example 1. To a four-necked flask equipped with a thermometer, a condenser and a nitrogen inlet tube, 160 g of 85% lactic acid aqueous solution and 13.6 g of acid clay were added, and the internal temperature and internal pressure were 105 ° C and 350 ° C, respectively, under a nitrogen stream.
Distilled water was removed by heating under reduced pressure for 6 hours while gradually increasing the temperature and the degree of reduced pressure from mmHg to 150 ° C. and 30 mmHg. Continue to set the internal pressure to 3 mmHg and the internal temperature to 175 ° C for 5
Heating was carried out for 0 hours. The reaction solution was cooled to room temperature, 400 ml of methylene chloride was added, dissolved with stirring, the acid clay was removed by excess (using Toyo Paper No. 131), and the solution was concentrated to dryness to give 100 g of almost white polymer. Got The weight average molecular weight and dispersity of this polymer were 22,000 and 1.75, respectively.

Regarding the residual catalyst in the obtained copolymer, the copolymer was placed on a platinum Petri dish and subjected to a sodium carbonate melting treatment, and then aluminum and silicon were subjected to the aluminone method and the molybdenum blue method, respectively. As a result of colorimetric determination, none was detected, and no catalyst was found to be mixed.

Example 2. Example 1 except that 27.2 g of aluminum silicate was used as the catalyst. Almost colorless polymer that reacts in the same manner as
92g was obtained. The weight average molecular weight and polydispersity index of this polymer were 21,900 and 1.70, respectively. The same was true when the catalyst was kaolin or talc.

Regarding the residual catalyst in the obtained copolymer, Example 1. As a result of detection of the residual catalyst in the same manner as in, no contamination of the catalyst was observed.

Example 3. Example 1. In the same manner as above, using 160 g of 85% lactic acid aqueous solution, 6.8 g of activated clay was charged in place of the acid clay, and the heating reaction after removing the distilled water was carried out at an internal pressure of 5 mmHg and an internal temperature of 185 ° C. for 96 hours. 90 g of polymer was obtained. The weight average molecular weight and dispersity of this polymer were 29,600 and 1.85, respectively.

Regarding the residual catalyst in the obtained copolymer, Example 1. As a result of detection of the residual catalyst in the same manner as in, no contamination of the catalyst was observed.

Example 4. Example 1 except that 160 g of 85% aqueous lactic acid solution, 38 g of glycolic acid and 17.4 g of activated clay were used. The same reaction was carried out to obtain 122 g of an almost white copolymer. The weight average molecular weight and dispersity of this copolymer were 20,100 and 1.70, respectively. Further, the obtained copolymer was analyzed by nuclear magnetic resonance spectrum as a deuterated chloroform solution. As a result, the copolymerization composition of lactic acid and glycolic acid was 76 mol%: 24 mol%.
(79.7% by weight: 20.3% by weight).

The catalyst remaining in the obtained copolymer is described in Example 1. As a result of detection of the residual catalyst in the same manner as in, no contamination of the catalyst was observed.

Example 5. After charging 160 g of 85% lactic acid aqueous solution, 17.5 g of glycolic acid and 9 g of acid clay, the heating reaction after removing distilled water was carried out at an internal pressure of 3 mmHg and an internal temperature of 170 ° C. for 96 hours to obtain 130 g of an almost white copolymer. . The weight average molecular weight and dispersity of this copolymer are 28.100 and 1.73, respectively,
The copolymer composition of lactic acid and glycolic acid is 89 mol%: 11 mol
% (90.9% by weight: 9.1% by weight).

Similar reactions and results were obtained when the catalyst was aluminum silicate, bentonite, or kaolin.

Regarding the residual catalyst in the obtained copolymer, Example 1. As a result of detection of the residual catalyst in the same manner as in, no contamination of the catalyst was observed.

Example 6. 202% by using 146 g of 93% lactic acid aqueous solution and 38 g of glycolic acid
Heat reaction at ℃ for 6 hours, weight average molecular weight 2,70
0, copolymer composition lactic acid: glycolic acid = 75mol%: 25mol%
To obtain a copolymer of

Example 1. 100 g of the obtained copolymer and 10 g of acid clay were placed in the same polymerization equipment as above, the internal pressure was set to 5 mmHg, and the internal pressure was 180 ° C.
And heated for 50 hours. The reaction solution was cooled to room temperature, added with 500 ml of methylene chloride, dissolved with stirring, the acidic clay was removed by excess (using Toyo Paper No.131), and the solution was concentrated to dryness to give almost white polymer 82 g. Got The weight average molecular weight and dispersity of this polymer were 23,700 and 1.73, respectively.
Furthermore, the copolymerization composition of lactic acid and glycolic acid is 75
It was 25% by mol (78.8% by weight: 21.2% by weight).

Regarding the residual catalyst in the obtained copolymer, Example 1. As a result of detection of the residual catalyst in the same manner as in, no contamination of the catalyst was observed.

Example 7. Lactic acid dimer (lactic acid lactate) 97 g, glycolic acid dimer (glycolic acid glycolate) 54 g and acid clay
Example 6, except that 7.5 g was used. The reaction was performed in the same manner as in (1) to give 98 g of an almost white copolymer. The co-weight average molecular weight and dispersity of this polymer are 21,000 and 1.75, respectively.
And the copolymer composition of lactic acid and glycolic acid is 59.5.
It was mol%: 40.5 mol%: (64.6 wt%: 35.4 wt%).

Regarding the residual catalyst in the obtained copolymer, Example 1. As a result of detection of the residual catalyst in the same manner as in, no contamination of the catalyst was observed.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-51-41327 (JP, A) JP-A-52-147691 (JP, A) JP-A-56-45920 (JP, A) Industrial chemistry magazine, No. 1 Vol. 67, No. 6 (1964), Asahara and Katayama, "Synthetic Reaction of Polylactide and Properties of Products", p. 956 ~ 961

Claims (1)

[Claims] 1. A polymer of lactic acid or glycolic acid, or a copolymer thereof, characterized by using an inorganic solid acid catalyst as a catalyst when polycondensing lactic acid and / or glycolic acid to produce a polymer. Polymer production method.