JPH09157368A - Purifying method for polylactic acid-polyethylene glycol-polyactic acid triblock copolymer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a purifying method whereby a crude polylactic acid- polyethylene glycol-polylactic acid triblock copolymer is purified into a triblock copolymer which has a narrow mol.wt. distribution and a narrow distribution of compsn. ratio and does not contain residual low-molecular components such as an unreacted monomer or an oligomer by using a specific fractional precipitation method. SOLUTION: A triblock copolymer of an ABA type (wherein A is a polylactic acid block formed from L-lactic acid and/or D-lactic acid; and B is a polyethylene glycol block) is produced by polymerizing lactide at its m.p. or higher in the presence of polyethylene glycol and a catalyst. The polymn. may be soln. polymn. in chloroform, though mass production by melt polymn. is industrially adopted. The mol.wt. of the copolymer is adjusted to 100-100,000 depending on the application. A crude triblock copolymer produced as above is purified by repeating fractional precipitation wherein a poor alcohol solvent capable of dissolving either polylactic acid or polyethylene glycol is added dropwise as the precipitant to a soln. of the triblock copolymer in a good solvent and the resultant precipitate is removed from the system.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a polylactic acid-polyethylene glycol-polylactic acid having a narrow molecular weight distribution and a narrow copolymer composition distribution, which is used for producing microcapsules, nanoparticles, nanocapsules and the like for pharmaceuticals and cosmetics. The present invention relates to a method for purifying a ternary block copolymer.

[0002]

2. Description of the Prior Art When polylactic acid-polyethylene glycol-polylactic acid ternary block copolymers having a wide molecular weight distribution are used to produce microcapsules, nanoparticles, etc. for pharmaceuticals and cosmetics, the obtained capsules and particles are Distribution occurs in disintegration time and causes an undesirable phenomenon such as disintegration of particles being biased in the initial stage. Therefore, the polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer used for such an application is preferably one having a narrow molecular weight distribution and a narrow copolymer composition distribution.

Polylactic acid-polyethylene glycol-polylactic acid ternary block copolymers having a narrow molecular weight distribution and a narrow copolymer composition distribution are usually produced by so-called living polymerization such as anionic polymerization and immortal polymerization. These polymerization methods are described, for example, in "Experimental Chemistry Course (4th Edition) Vol. 28, Polymer Synthesis" (edited by the Chemical Society of Japan), pages 208-217.
Although it is a known method as described in J., there is a problem that the method of living polymerization is extremely complicated,
It is not a suitable method for industrial mass production.

As a method for separating raw materials of a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer having a wide molecular weight distribution and a wide copolymerization composition by the molecular weight and the copolymerization composition, a porous material is used. There is known a method of utilizing a difference in properties of a polymer in a solution such as a diffusion rate in a gel medium or a functional gel medium, adsorption and distribution. As such a method, for example, as described in "Polymer Alloy" (edited by Tadao Odaka, published by Tokyo Kagaku Dojin), page 40, fractionation of the copolymerization composition is carried out by thin layer chromatography. Then, a method is known in which gel filtration is used to perform fractionation based on the difference in molecular weight. However, this method requires the use of a polymer solution having an extremely low concentration (usually 1% by weight or less), the operation for recovering the polymer from the solution after the treatment is complicated, and a large amount of waste liquid is produced. There are problems such as.

[0005]

The inventors of the present invention have completed the present invention as a result of intensive research conducted in view of the above-mentioned problems of the prior art. The purpose is to obtain (1) a narrow molecular weight distribution from the raw material of the polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer, and (2)
(3) To provide a purification method for obtaining a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer having a narrow distribution of copolymerization composition ratio and (3) not containing low molecular weight residues such as monomers and oligomers. is there.

[0006]

The object of the present invention is to provide a method for purifying a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer dissolved in a good solvent by a fractional precipitation method using a precipitating agent. This is achieved by a method for purifying a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer, wherein a precipitant that is a poor solvent for only one of polylactic acid and polyethylene glycol is used.

The method for measuring and displaying the molecular weight distribution in the present invention is the ratio of the weight average molecular weight (Mw) to the number average molecular weight (Mn) obtained from the main peak measured by gel permeation chromatography (GPC) ( Mw / M
n), and the reduced molecular weight 1000 determined by GPC
It is evaluated by two parameters of the ratio (Ps / Pm) of the sub-peak area (Ps) to the main peak area (Pm) corresponding to the following.

In the present invention, the narrow molecular weight distribution means that the above Mw / Mn is 3 or less, preferably 2.5 or less, more preferably 2.0 or less, still more preferably 1.5 or less, and Ps / Pm. Value of 5% or less, preferably 2.5
% Or less, more preferably 2.0% or less, still more preferably 1% or less. A large value of Mw / Mn or Ps / Pm, that is, one having a wide molecular weight distribution is a physical property of a polymer that is sensitive to the molecular weight, for example, solubility, crystallinity, crystallization rate, viscosity, etc. Has a wide distribution, which is not preferable for applications in which it is necessary to precisely control these physical properties.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer according to the present invention is a polymer (A) and a polyethylene glycol (B) consisting of L-lactic acid and / or D-lactic acid components. Is ABA
It is a ternary block copolymer block-polymerized into a mold.

The molecular weight of polyethylene glycol in the ABA type ternary block copolymer may be appropriately selected according to the intended use, but is usually 100 to 100,000.
And preferably 1,000 to 20,000,
More preferably, those of 3,000 to 10,000 are used. Polyethylene glycol may be polymerized by ring-opening polymerization of polyethylene oxide by a conventional method, but a commercially available product that is easily available can also be used. As such polyethylene glycol, for example, 1 of “Twelfth Amended Japanese Pharmacopoeia” (published by Daiichiho Publishing Co., 1991)
Suitable examples are Macrogol 6000 and Macrogol 2000 described on page 066.

The polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer according to the present invention uses the above-mentioned polyethylene glycol as an initiator and a catalyst,
It can be synthesized by ring-opening polymerization of a cyclic dimer (lactide) of L-lactic acid or / and D-lactic acid.

Any polymerization method may be used as long as it is industrially inexpensive and can be mass-produced. Examples of such a method include solution polymerization in chloroform, and the melt polymerization method is industrially preferably used. That is, while flowing dry air or dry nitrogen, the raw material polyethylene glycol and lactide are put into a polymerization tank equipped with a stirring blade, and heated to a temperature higher than the melting point of lactide and stirred. Then 0. to the total weight of lactide.
The catalyst is added at 0001 to 1% by weight, preferably 0.001 to 0.1% by weight, more preferably 0.02 to 0.08% by weight, and the temperature is 100 to 220 ° C, preferably 105 to 105 ° C.
Polymerization is promoted by stirring at 200 ° C., more preferably 110 to 160 ° C. in a heat retaining state.

When the polymerization temperature is higher than the melting point of polylactic acid, the reaction product is taken out of the system after reacting for a predetermined time. When the polymerization temperature is lower than the melting point of polylactic acid, the polylactic acid is crystallized as the polymerization proceeds, the reaction liquid becomes cloudy, and the viscosity rapidly increases. In this case, the stirring is appropriately stopped, and the polymerization is continued only by heat retention.

To carry out the melt polymerization, the raw material monomer and the catalyst are agitated, mixed and deaerated in a molten state by using, for example, a twin-screw kneading extruder with a vent or an apparatus having a stirring and feeding function similar thereto. While taking out continuously, it can be mentioned.

The catalyst used for the above polymerization is not particularly limited as long as it is a catalyst used for the polymerization of ordinary polyesters and a catalyst used for the polymerization of lactic acid and lactide. For example, compounds having catalytic activity shown in "Saturated Polyester Resin Handbook" (edited by Kazuo Yuki, published by Nikkan Kogyo Shimbun) can be used. Specific examples of such catalysts include tin halides such as tin chloride, organic acid tin such as tin 2-ethylhexanoate, organic alkali metal compounds such as butyl lithium and potassium t-butoxide, metal porphyrin complexes, and diethyl ether. A metal alkoxide such as aluminum methoxide is preferably used.

The fractional precipitation method using a precipitating agent in the present invention means a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer solution dissolved in a good solvent and kept at a constant temperature at a predetermined temperature. While dropping the poor solvent as a precipitant, the generated precipitate is taken out of the system. The precipitate obtained by this operation is a copolymer having a higher molecular weight than the polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer, which is the starting material, and containing a large amount of a polymer insoluble in the poor solvent. is there. By repeating this fractionation operation, the polymerization product as the raw material can be fractionated by the molecular weight and the copolymerization composition, and each fraction has a narrow molecular weight distribution and a narrow copolymerization composition distribution. Glycol-polylactic acid ternary block copolymer collects.

Here, the good solvent is an organic solvent capable of dissolving both polylactic acid and polyethylene glycol, and examples of such a solvent include a halogen-based good solvent. As the halogen-based organic solvent,
Examples thereof include aliphatic halides such as chloroform, carbon tetrachloride and trichloroethane, and aromatic halides such as trichlorobenzene, but not limited to these.

The poor solvent used in the present invention is an organic solvent which is soluble in either one of polylactic acid or polyethylene glycol but not in the other,
When the copolymerization composition of polylactic acid is large, an alcohol-based poor solvent is preferable. Here, the alcohol poor solvent is a solvent of alcohol alone or a mixed solvent containing alcohol as a main component. Examples of the alcohol include primary alcohols such as methanol and ethanol, secondary alcohols such as isopropanol, tertiary alcohols such as t-butyl alcohol, and diols such as ethylene glycol and triethylene glycol.

As the sub-component which is mixed with the above alcohol to form a mixed solvent, for example, the above-mentioned halogen-based good solvent, ketones such as acetone, lower aliphatic solvent such as hexane, aromatic solvent such as benzene and toluene. Can be used. The mixing ratio of these varies depending on the molecular weight to be separated and the copolymerization composition, but it is usually preferable to mix at 300% by weight or less with respect to the alcohol as the main component.
The mixed composition is not limited to this as long as the obtained acor-based mixed poor solvent has the ability to cause precipitation by dropping.

The concentration of the polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer dissolved in the above good solvent varies depending on the molecular weight and the copolymerization composition of the terpolymer, but is usually 1 to 50% by weight, It is preferably prepared in the range of 1 to 25% by weight. Further, the poor solvent is added dropwise to this solution while being kept at a predetermined temperature, and the temperature of the solution at this time is appropriately set below the boiling point of the solvent used.

The temperature of the white turbidity after the precipitation is formed by dropping a poor solvent is raised or lowered, and once the precipitate is dissolved, it is slowly returned to the original temperature again to form the precipitate, thereby separating the fractions. The accuracy can be increased, but this operation is not always necessary.

The method of removing the produced precipitate from the system is as follows:
For example, a centrifugal separation method, a method of separating a supernatant (or a supernatant) separated by allowing to stand naturally, a method of filtering and the like are used, but the method is not limited to this. Another effect of the fractionation method of the present invention is that the catalyst coordinated to the polymer terminal can be removed in the fractionation process.

[0023]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below with reference to specific embodiments. Before that, various measuring methods in this specification will be described.

[Molecular weight] Column G3000 manufactured by Tosoh Corporation
H, G3000H, G2000H, (each 0.78 mmφ
X30 cm), chloroform was used as an eluent, and the elution volume of the sample was determined at a temperature of 35 ° C. The number average molecular weight (Mn) and the weight average molecular weight (Mw) were calculated as converted molecular weights from a molecular weight calibration curve prepared using standard polystyrene.

[Copolymerization composition ratio] The copolymerization composition was determined from the ratio of the respective peak areas corresponding to polyethylene glycol and polylactic acid using an NMR measuring apparatus Bruker AM300.

Example 1 Polyethylene glycol having a number average molecular weight of 6000 was added to 1.
151 g of 5 g and L-lactide (made by Boehringer)
g and 0.1 g of tin 2-ethylhexanoate were dried, and then heated to 135 ° C. with stirring in a flask flushed with dry nitrogen. 1 at constant temperature after reaching 135 ℃
Allowed to react for hours. The obtained polymerization product was white and had a weight average molecular weight of 550,000, Mw / Mn of 5, and Ps / Pm of 5%. This was designated as fraction f0.

The obtained raw material, a polymerization product, was dissolved in chloroform to prepare a solution having a polymer concentration of 10% by weight. 1 liter of this solution was placed in a flask and kept at 25 ° C. in a constant temperature bath. A 1: 1 mixed solvent of methanol / chloroform was added dropwise to this solution until a white precipitate appeared.
When the temperature of the white solution was raised to 60 ° C., the precipitate disappeared and returned to a transparent liquid. When the temperature of this liquid was lowered at a rate of about 5 ° C./10 minutes and returned to the original temperature of 25 ° C., precipitation again occurred. When stirring was stopped and left at a constant temperature overnight,
The precipitate settled to the bottom of the flask. Pump off the supernatant liquid, transfer to a new flask, again under constant temperature,
A 1: 1 mixed solvent of methanol / chloroform was added dropwise until a white precipitate appeared. The same operation as described above was repeated to separate the precipitate from the supernatant. The respective precipitates taken out were designated as f1, f2 and f3 from the beginning. From f0 to f3,
The Mw / Mn, Ps / Pm and copolymer composition were as shown in Table 1.

[0028]

[Table 1]

Examples 2 to 8 Polyethylene glycol used in Example 1 and L-
Polymerization products were obtained in the same manner as in Example 1, except that the charged composition of lactide was changed as shown in Tables 2 and 3. The molecular weight, the molecular weight distribution and the composition ratio of the fraction corresponding to the fraction f2 of Example 1 were as shown in Tables 2 and 3. Also,
A comparison with the theoretical curve of the molecular weight calculated assuming that the polymerization proceeds from both ends of polyethylene glycol by a chain reaction is shown in FIG. The plot is the measured value. There is good agreement between theory and experiment, and the obtained polymerization product is a so-called A in which polylactic acid-polyethylene glycol-polylactic acid is combined.
It was clearly shown to be a BA type ternary block copolymer.

[0030]

[Table 2]

[0031]

[Table 3]

Example 9 L-lactide having an optical purity of 99.8% that had been sufficiently dried (water content of 100 ppm or less) and had been melted in advance, and polyethylene glycol having a number average molecular weight of 8200, which had been dried and melted, had a ratio of 97/3. Was fed to the raw material supply section of the twin-screw kneader. At the same time, as a polymerization catalyst, 0.3 against lactide
% Tin dioctylate was added. The twin-screw kneader used was a combination of a large number of screws with a diameter of 30 mm and a stirring element with a two-blade shape and a thickness of 7 mm, and a feed screw and other parts for the raw material supply part and the two vent holes. Was equipped with a stirring element. The cylinder had a circular cross section with a constricted central portion, the temperature was 190 ° C., nitrogen gas was supplied from the first vent hole, and exhausted from the second vent hole. The two rotating shafts rotate in the same direction, and the rotation speed is
It was 60 times / minute.

The polymer discharged from the above twin-screw kneader is
It is supplied to a second biaxial kneader with a diameter of 40 m and two vent holes connected to the shaft kneader, and the temperature of the cylinder is 1
At 90 ° C., the rotation speed was 40 ° C./min in the same direction, a small amount of nitrogen gas was supplied from the first vent, the second vent was connected to a vacuum pump, and the degree of vacuum was maintained at about 0.5 Torr. . The polymer discharged from the second twin-screw kneader was fed with pressure by a gear pump, filtered through a 20 μm filter, and the diameter was 2
It was extruded from a nozzle of mm, cooled with water to solidify, and then cut to obtain chips. The average residence (reaction) time of the polymer in the first biaxial kneader was 5 minutes 30 seconds, the residence time in the second biaxial kneader was 16 minutes, and the total average polymerization time was 21 minutes 30. Seconds. The chip was not colored and had excellent transparency.

The weight average molecular weight of the obtained chips was 61,
000, Mw / Mn was 5, and Ps / Pm was 25%. Using this as a raw material (G0), the fractionation was repeated by the scheme shown in FIG. Mw and Mw / M of each obtained fraction
The n, Ps / Pm, and the copolymer composition were as shown in Table 4.

[0035]

[Table 4]

[0036]

[Brief description of the drawings]

FIG. 1 is a graph showing a comparison between measured and theoretical molecular weights.

FIG. 2 is a fractional diagram showing a separation scheme of a raw material (G0).

Claims (2)

[Claims] 1. When purifying a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer dissolved in a good solvent by a fractional precipitation method using a precipitant, either polylactic acid or polyethylene glycol is used as the precipitant. A method for purifying a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer, which comprises using a poor solvent for only one of them. 2. The method for purifying a polylactic acid-polyethylene glycol-polylactic acid ternary block copolymer according to claim 1, wherein the good solvent is a halogen solvent and the poor solvent is an alcohol solvent.