JPS62280220A - Production of high-mw polylactide or polyglycolide - Google Patents

Abstract

PURPOSE:To obtain inexpensively the title slow-releasing polymer useful as, e.g., a slow-releasing matrix for medicines, agricultural chemicals, etc., by reacting a low-MW polylactide or polyglycolide or a condensate thereof with a specified acid chloride and subjecting the product to a melt polycondensation reaction, etc. CONSTITUTION:Lactic acid and/or glycolic acid are polycondensed at 150-250 deg.C for 1-10hr in the presence (absence) of a catalyst such as a tin compound in a vacuum or a stream of an inert gas to obtain a low-MW polylactide, polyglycolide or cocondensate thereof of a number-average MW of 1,000-6,000. The product is dissolved in an organic solvent such as toluene to form a solution of a concentration of 5-60wt% and this solution is reacted with an acid chloride selected from a dichloride compound (e.g., succinyl chloride) and thionyl chloride, heated in a vacuum or a stream of nitrogen gas to remove the organic solvent and either melt-polycondensed at 150-250 deg.C for 1-10hr or reacted at 30-100 deg.C for 1-8hr after adding an amine compound such as trimethylamine to increase the MW to about 40,000. The title polymer can thus be obtained.

Description

Detailed Description of the Invention 3. Detailed Description of the Invention (Industrial Application Field) The present invention relates to the production of polylactide, polyglycolide, or copolycondensates thereof obtained by dehydration polycondensation reaction of ceric acid and glycolic acid. Regarding the method, it is an object of the present invention to provide a high molecular weight polylactide, polyglycolide, or a copolycondensate thereof, which is useful as a sustained release polymer.

Polylactide, polyglycolide, or their copolycondensates are used as sustained-release polymers for biodegradable medical materials such as sutures, agricultural chemical compositions for soil treatment such as herbicides and soil fungicides, and base materials for microcapsules. In recent years, it has been used in many ways.

In the case of agricultural chemical compositions, the sustained-release polymer must have a suitably high molecular weight to release the drug component over a long period of time. In addition, when used as a medical material, it is necessary for the polymer material to maintain the necessary strength until it fuses with the living body, and then be quickly decomposed and absorbed. is required.

(Prior art) As a method for obtaining high molecular weight polylactide, polyglycolide, etc., there is generally known a method in which lactide and glycolide are produced from 1-esteric acid and glycolic acid, and then 611-ring polymerization is performed to produce polylactide and polyglycolide. However, although this method allows the production of lactide and glycolide with high molecular weight, it requires a great deal of labor and cost to prepare lactide and glycolide, making it uneconomical.
There is a method to obtain polylactide and polyglycolide directly from glycolic acid, but while this method is a simple polycondensation method, it requires high molecular weight polycondensation! I can't get it.

(Problems to be Solved by the Invention) Therefore, in order to obtain an inexpensive polycondensed metal product with a high molecular weight, the present inventors conducted an investigation using a direct polycondensation method from 1-esteric acid and glycolic acid.

The direct polycondensation reaction of fL acid and glycolic acid is a sequential reaction similar to the esterification reaction between a dibasic acid and a polyhydric alcohol, and the molecular weight increases with reaction time. However, this reaction is an equilibrium reaction and its equilibrium constant is extremely small, so a catalyst is required to increase the molecular weight.

Generally, metal salts, metal oxides, etc. are used as this type of catalyst, but 1LP! ! In the case of oxyacids such as glycolic acid, even if ester bonds are formed in the fL condensation reaction, they also have the effect of decomposing the polymer, so it has been difficult to obtain polycondensed metal products with a high molecular weight due to this effect.

(Means for Solving the Problems) Based on these findings, the present inventors developed a direct dehydration polycondensation method for lactic acid and glycolic acid in order to obtain high molecular weight polylactide, polyglycolide, or copolycondensates thereof. We have conducted intensive research on methods for further increasing the molecular weight of polycondensates obtained from The present invention was completed based on the discovery that it is easy to further increase the molecular weight of the polycondensate by carrying out the reaction or adding an amine compound.

That is, the present invention involves reacting low molecular weight polylactide, polyglycolide, or a copolycondensate thereof with an acid chloride selected from a dichloride compound or thionyl chloride, and then performing a melt polycondensation reaction, or The present invention relates to a method for producing high molecular weight polylactide, polyglycolide, or a copolycondensate thereof, which comprises adding and reacting a compound.

(Function) The monomers used in the present invention are lactic acid and glycolic acid, and 1L acid may be either D-type or L-type, or racemic.

There are no particular limitations on the concentrations of these when performing the reaction, but if the concentration at the start of the polycondensation reaction is low, the amount of oligomers etc. produced at the end of the reaction will increase and the yield will decrease. If the monomer concentration is low, it is desirable to concentrate the mixture appropriately before use.

! ! Reduced scale reaction, fL acid, glycolic acid, or a mixture of lactic acid and glycolic acid, without catalyst or after adding a tin compound etc. as a catalyst, under reduced pressure or under the introduction of an inert gas such as nitrogen gas, to 150 to 250 This is done while warming to °C.

After the start of the reaction, the molecular weight of the polycondensate increases gradually, and the number average molecular weight of the polycondensate increases from 1000 to 6 within 1 to 10 hours after the start of the reaction.
The range is 000. The molecular weight of the polylactide, polyglycolide, or copolycondensate thereof used in the present invention (molecular weight of polylactide, polyglycolide, or copolycondensate thereof) is usually within this range, and there is no problem in using one with a molecular weight exceeding 6,000. It is difficult to directly obtain a substance in this range by a dehydration polycondensation method, and it is economically undesirable to use a substance exceeding this range.In addition, if the molecular weight is less than 1000, the high molecular weight of the present invention It becomes extremely difficult to obtain a condensate.

The number average molecular weight of the polycondensate, which increases sequentially during the polycondensation reaction, is determined by sampling the reaction solution at regular intervals and measuring the molecular weight using the following method.

Molecular weight measurement method> About 1g of the reaction solution was added to 20ml of benzyl alcohol for 1 hour.
After heating and cooling, titrate with 0.025N potassium hydroxide in benzyl alcohol using phenolphthalein as an indicator. Titration is performed under a nitrogen atmosphere while introducing N2 gas to remove interference such as carbon dioxide in the air.

The molecular weight of the polycondensate is determined from the 111i2 value using the following formula.

However, W: Polycondensation weight (g) f: Q, 025N potassium hydroxide? Factor S of 8 liquids: °
2 drops (7°) (ml) B:
° Titration amount (7″′V) (ff
ll) Mn= Number average molecular weight of the polycondensate In this method, the molecular weight is calculated from this value by quantifying the amount of carboxyl groups at the end groups of the polycondensate. Mean molecular weight.

The polylactide, polyglycolide, or condensate thereof obtained in this way is dissolved in an organic solvent at 5 to 60 fflff.
Dissolve at a concentration of i%.

Any organic solvent may be used as long as it dissolves the above polycondensate, including benzene, chlorobenzene,
Commonly used are l.luene, xinin, tetrahydrofuran, dioxane, and the like.

Next, in the present invention, an acid chloride is added to this polycondensate solution to activate the polycondensate terminal group by converting it into acid chloride. As the acid chloride used in the present invention, thionyl chloride or oxalyl chloride which is a dichloride compound,
Examples include succinyl chloride and terephthaloyl dichloride.

In addition, when using acid chlorides other than these, for example, monochloride compounds such as acetyl chloride, propionyl chloride, benzoyl chloride, etc., it is possible to convert the terminal group into acid chloride, but it is possible to convert the terminal group into acid chloride. I can't.

Further, the acid chloride is used in an amount of 0.25 to 2 moles based on the amount of carboxyl groups at the end of the molecular chain of the polycondensate. That is, if it is less than 0.25 mol, the high molecular weight of the present invention cannot be achieved, and if it exceeds 2 mol, even if high molecular weight is possible, the result is that the acid chloride is contained in a large amount in the polycondensate. This is less preferable than inducing deterioration of the obtained high molecular weight gL polycondensate and lowering the molecular weight.

The amount of carboxyl groups at the molecular chain ends of the single polycondensate mentioned above is calculated by the following formula from the number average molecular weight of the polycondensate calculated by the above molecular weight measurement method.

X= − n However, X: carboxyl group i (mol/g) of polycondensate +
1n: Number average molecular weight of polycondensate The reaction after addition of acid chloride is 0.5 at a temperature of 20 to 100°C.
Carry out under stirring for ~10 hours.

The relationship between temperature and time at this time is generally contradictory, with 8 hours at 20°C, 4 hours at 60°C, and 100
At 0C, it takes 1 hour.

The polycondensate solution obtained after the reaction with the acid chloride is heated appropriately under reduced pressure or while introducing nitrogen gas to remove the organic solvent, and then heated to 150-250°C. The high molecular weight polycondensate of the present invention can be obtained by heating and performing a melt polycondensation reaction for 1 to 10 hours.

On the other hand, the polymer monopolycondensate of the present invention can also be obtained by adding an amine compound to the polycondensate solution after the reaction with the acid chloride.

As a method, first, trimethylamine, triethylamine, tripropylamine, tributylamine, lysine, etc. are used as amine compounds, and 0.5 ~
It is added in a proportion that is in the range of 2 moles. By reacting this at a reaction temperature of 30 to 100°C for 1 to 8 hours, the high molecular weight polycondensate of the present invention can be obtained.

The high molecular weight polylactide of the present invention obtained in this way,
The molecular weight of polyglycolide or their co-condensates is high, and the molecular weight of the polycondensate produced by f'F in a normal direct dehydration polycondensation method is about 4,000 in a system without a catalyst, and about 4,000 in a system with a catalyst such as a tin compound. While 7000 is the limit for each,
According to the method of the invention, this molecular weight can be increased to about 40,000.

Therefore, since the product of the present invention has a high molecular weight, the decomposability of the polycondensate is extremely low, and when the polycondensate is molded, it has excellent properties such as high strength. Therefore, sustained release bases can be used, for example, as raw materials (absorbent materials, sustained release matrices for pharmaceuticals, agricultural chemicals, etc.), microcapsule bases, soil conditioners, as well as disintegrating agricultural films, It can be used in a wide range of applications such as surfactants, fruit quality improvers, and gas separation permeable membranes.

Furthermore, the product of the present invention has extremely low degradability up to a certain period of time and then rapidly decomposes, which is not possible with the conventional direct dehydration polycondensation method. When applied to a sexual matrix, it has the advantage that the polycondensate base decomposes quickly to release the drug.

(Example) The present invention will be described below with reference to Examples, but the present invention is not limited thereto.

It should be noted that all percentages are by weight unless otherwise specified.

Example 1 500ffi equipped with stirrer, thermometer and condenser
90% L-Tel in a three-bottle flask, @400
(Put in, under stirring, temperature 85°C, degree of vacuum 100mm)
In Hg, L-=1. After approximately 45 g of water after concentrating the acid flowed out, the temperature and degree of vacuum were gradually increased, and the reaction was carried out at 200°C, 1L, and 5mmHg for 12 hours.

The number average molecular weight of the polycondensate obtained at this time was 3,100.

Example 2 200 equipped with N2 gas introduction pipe, thermometer, and condenser
In a 1111 volume glass reactor, 90% L-7L acid 90%
Add 60.8 g of glycolic acid and 300 g of N2 gas.
While blowing into the solution at a flow rate of m1/min, the temperature was increased to 2.
Raise the temperature to 05°C. The reaction was carried out for 10 hours while maintaining this temperature.

The number average molecular weight of the normal condensate obtained at this time was 3200. Example 3 400 g of 90% DL-lactic acid was placed in the same flask as in Example 1, and the mixture was stirred at a temperature of 90°C and a degree of vacuum of 100 mmHg.
-'C-0L-1 acid was concentrated.

After approximately 45 tons of water had spilled, stannous chloride (Snclp)
018g of 2HaO) was added, the temperature and degree of vacuum were gradually increased, and the reaction was carried out at 205°C, 110C11O for 8 hours.

The number average molecular weight of the polycondensate obtained at this time was 6,000.

Example 4 100 g of the polycondensate obtained in Example 1 (carboxyl at the end of the molecular chain, 3.23 x 10-' mat/g) was ground, placed in the same flask as in Example 1, and mixed with benzene 20
0ml was added and the polycondensate was dissolved under stirring.

To this, thionyl chloride and various acid chlorides shown in Table 1 were added in predetermined amounts, and a reaction was carried out at 82°C for 14 hours.

Next, the degree of decompression is 1001! After removing benzene at 111 Hg, the reaction was carried out at 205°C and a reduced pressure of 15 mmHg for 4 hours.

The polycondensate after the reaction was dissolved in 200 ml of chloroform, then precipitated in a large amount of methanol, further washed with methanol, and then vacuum-dried overnight at 30°C.

The number average molecular weight of the polycondensate thus obtained was measured and the results are shown in Table 1.

Example 5 100 g of the polycondensate obtained in Example 2 (carboxyl group at the end of the molecular chain 13.L3XIQ-'mol/g) was ground, placed in the same flask as in Example 1, and mixed with toluene 2
00i1 was added and the polycondensate was dissolved under stirring.

To this, 4.8g of oxalyl chloride (3,38X10-2m
ol) was added thereto, and the reaction was carried out at 78°C for 6 hours.

Next, 4.0 g of triethylamine (3,96×10-
2 mol) was gradually added dropwise to the reaction system, and the reaction was carried out at 83°C for 2 hours.

The polycondensate after the reaction was precipitated in a large amount of methanol, further washed with methanol, and then vacuum-dried overnight at 30°C.

The number average molecular weight of the polycondensate of the present invention thus obtained was 17
It was 800.

Example 6 Bog of the polycondensate obtained in Example 3 (carboxyl group at the end of the molecular chain jJf 1.29X10-'mol/g)
was crushed and placed in the same flask as in Example 1, and xylene 25011 was added thereto to dissolve the polycondensate under stirring.

Con i: i conversion"f kushi=ru3.Og(1,9
4×10 −2 mal) was added, and the reaction was carried out at 85° C. for 5 hours.

Next, after removing xylene at a reduced pressure of 50 mmHg,
The reaction was carried out for 5 hours at 20υC, iJ & pressure 8mIIIHg.

The polycondensate after the reaction was dissolved in 300 ml of chloroform, then precipitated in a large amount of methanol, further washed with methanol, and air-dried at 30°C.

The number average molecular weight of the polycondensate of the present invention thus obtained was 37.
It was 700.

Example 7 Using the polycondensates of the present invention and comparative example obtained in Example 4,
The hydrolyzability of the polycondensate was investigated.

The test method involves crushing these polycondensates into 24-48 m
esh in a 50ml screw bottle.
0 g each was taken, 30 ml of water was added, the mixture was sealed, and the mixture was stored at a constant temperature of 37°C.

After this was left for a predetermined period of time, the dry amount of the polycondensate was measured, and the hydrolysis rate of the polycondensate was determined using the following formula.

However, the hydrolysis rate (%) of Y-polycondensate W: Weight of i-condensate after drying (g) The results are shown in Table 2.

Table 2

Claims (1)

[Claims] After reacting a low molecular weight polylactide, polyglycolide, or a copolycondensate thereof with an acid chloride selected from a dichloride compound or thionyl chloride, a melt polycondensation reaction is performed or an amine compound is added to the reaction. A method for producing a high molecular weight polylactide, polyglycolide, or a copolycondensate thereof, comprising: