JPS6264823A - Production of polyglycolide or polylactide - Google Patents

Abstract

PURPOSE:To obtain a high-MW polyglycolide inexpensively, by polycondensing glycolic acid in the presence of a catalyst and adding liquid paraffin to the reaction system after reaching a specified MW. CONSTITUTION:Glycolic acid is polycondensed at 150-250 deg.C in the presence of 0.01-1.0wt%, based on the acid, catalyst (e.g., stannous chloride). When the MW of the condensate reaches 2,000-6,000 after about 2-10hr from the start of the reaction, 5-30wt%, based on the acid, liquid paraffin is added to the reaction system and the reaction is further continued for about 1-20hr. This process is useful also for the production of a polylactide from lactic acid.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a method for producing polycricoli-1- and polylactide obtained by dehydration polycondensation reaction of glycolic acid and lactic acid, which are particularly useful as sustained-release polymers. The purpose of this invention is to provide a high molecular weight polycricolide, Vorilacti 1.

Polycricolide and Vorilacti 1~ are used as sustained release polymers for biodegradable medical materials such as sutures, and agricultural chemical compositions for soil treatment such as herbicides and soil fungicides.

In recent years, F has been widely used as a base material for microcapsules, etc.
This is being used.

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

(Prior art) A generally known method for obtaining high molecular weight polyglycolide and polylactide is to produce glycolide and lactide from glycolic acid and 4L acid, and then ring-opening polymerize them to produce polyglycolide and polylactide. However, although this method yields products with high molecular weight, glycolide,
The production of lactide requires a great deal of labor and expense;
Not economical. Another method is glycolic acid,
Polyglycolide directly from lactic acid.

Is there a method for obtaining polylactide? Although this method is a simple polycondensation method, it does not yield a high molecular weight polycondensate.

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

The direct polycondensation reaction of glycolic acid and lactic acid is a sequential reaction similar to the esterification reaction between a dibasic acid and a polyhydric alcohol, and the molecular weight increases with the reaction time.

In addition, the water molecules produced at this time have the effect of lowering the molecular weight of the polycondensate, which increases successively in the polycondensation reaction, by its hydrolytic action, so it is possible to remove the water produced during the polycondensation from the reaction system. , is an important factor for increasing the molecular weight.

Methods for removing the generated water molecules from inside the reaction system to outside the reaction system include a mechanical method of increasing the stirring speed during the reaction, a method of increasing the degree of vacuum, and a method of increasing the N2 gas flow rate when introducing N2 gas into the reaction system. There are methods to volatilize and remove water molecules by increasing the
Removal of water molecules becomes difficult as the reaction progresses.

Therefore, it is important to suppress the rising viscosity of the reaction solution and to efficiently remove the water generated as the reaction progresses out of the reaction system by the above-mentioned operation in order to increase the molecular weight of the polycondensate. It is a method.

(Means for Solving the Problems) Based on these findings, the present inventors have conducted intensive research to obtain high molecular weight polyglycolide or polylactide through the dehydration polycondensation reaction of glycolic acid and lactic acid. It has been discovered that the use of liquid paraffin suppresses the increase in viscosity within the reaction system and effectively increases the diffusion rate of water, thereby making it possible to obtain a high molecular weight polycondensate, and has developed the present invention. It is completed.

That is, the present invention relates to a method for producing polyglycolide or polylactide, which comprises using liquid paraffin during polycondensation, and the present invention relates to a method for producing polyglycolide or polylactide, which comprises using liquid paraffin during polycondensation. The present invention relates to a method for obtaining polyglycolide and polylactide.

(for production) The chemical compound used in the present invention is glycolic acid.

Lactic acid may be either D-type or L-type, or racemic.

There are no particular limitations on the concentrations of these components when carrying out the reaction, but if the concentration at the start of the polycondensation reaction is low, the amount of oligomers etc. produced at the beginning of the reaction will increase and the yield will decrease. When the monomer concentration is low, it is desirable to perform appropriate concentration before use.

The polycondensation reaction method usually uses a catalyst and
After adding a catalyst, the reaction is carried out while heating to 150 to 250° C. under sealed reduced pressure or while introducing an inert gas such as a nitrogen gaff.

The catalysts used include stannous chloride, stannous sulfate,
No. 1 oxide, No. 2 oxide, tetraphenyltin, metal tin powder, titanium tetrachloride.

Zinc oxide, antimony oxide, antimony chloride.

Lead oxide, calcium oxide, nutrontium oxide.

Oxidation 7/l/ Minirum, iron oxide, calcium chloride.

Zinc acetate, P-1 luenesulfonic acid, etc. can be used.

There are no particular limitations on the amount of these added, but usually 0 to 1 monomer of glycolic acid or lactic acid.
It is used in a range of 0.01 to 10% by weight.

After the start of the reaction, the molecular weight of the polycondensate increases gradually, and in the present invention, liquid paraffin is added when the molecular weight is in the range of 2,000 to 6,000. The addition of liquid paraffin suppresses the increase in viscosity and the number of fibers, and the water that is successively produced is easily diffused into the reaction yarn 1 and removed.

- To determine the molecular weight of the polycondensate in the column, sample the reaction solution at regular intervals and measure the molecular weight using the following method.

<Molecular weight measurement method> About 12 of the reaction f4ft was heated and dissolved in 20me pencil alcohol, and after cooling, phenolphthalein was added as an indicator e.
This is then titrated with a 0.025N potassium hydroxide solution in benzyl alcohol. During the titration, in step 1, nitrogen gas is introduced in order to remove interference such as carbon dioxide in the air, and the titration is carried out under a nitrogen atmosphere.

The molecular weight of the polycondensate is determined from the titration value using the following formula t.

0025f (S-13) However, W, polycondensation weight (y) f: o, factor S of 025N potassium hydroxide melt flower
// Titration amount (sample) B
// Titration amount (≠ rank) Mn: Number average molecular weight of the polycondensate In addition, in this method, the molecular weight is calculated from this value by quantifying the amount of carbogyyl groups of the terminal groups of the polycondensate. Moreover, the molecular weight referred to in the present invention refers to the number average molecular weight.

The molecular weight of the polycondensate decreases to 20% approximately 2 to 10 hours after the start of the reaction.
00 to 6000, or liquid paraffin is added within this range.

In the present invention, the timing of addition of this liquid paraffin is particularly important; the molecular weight of the polycondensate is less than 2000, or
If it is added at a point exceeding 0.000, it is not possible to obtain a high molecular weight polycondensate.

Regarding the proportion of liquid paraffin used, it varies depending on the monomers used, the type of catalyst, the concentration, the reaction temperature, etc., but it is generally used in the range of 5 to 30 M% relative to the monomer amount of glycolic acid or lactic acid. .

That is, if the amount of liquid paraffin is less than the lower limit, the effect of the present invention cannot be expected, and if the liquid paraffin is added in excess of the upper limit, it will conversely inhibit the volatilization of water into the series, making it difficult to obtain a high molecular weight polycondensate. Can not.

After adding the liquid paraffin, the reaction is continued for about 1 to 20 hours, thereby obtaining the polycondensate of the present invention. In addition, the method of adding liquid paraffin is as follows: molecule i: 2000~
It may be continuous or intermittent within the range of 6000.

(Effect of the invention) The molecular weight of the polycondensate obtained by the method of the invention is high;
While the number average molecular weight of polycondensates obtained without using liquid paraffin is usually limited to about 7,000, according to the method of the present invention, the molecular weight can be reduced to about 1,000.
It can be removed.

Furthermore, by applying the method of the present invention to the method of obtaining polyglycolide and polylactide by ring-opening polymerization from glycolide and lactide described above, it is possible to obtain polycondensates with higher molecular weight. Needless to say.

Since the polyglycol 1- or polylactide produced by the method of the present invention has a high molecular weight, it has excellent properties such as high strength. Drug sustained release mal-IJ such as
It has a wide range of uses, including not only Kunu, Microcuff 9-cell base, and soil conditioner, but also disintegrating agricultural films, surfactants, fruit quality improving agents, gas separation permeable membranes, etc.

(Examples) In order to explain the present invention in more detail, the present invention will be described below with reference to Examples, but the present invention is not limited thereto.

In this example, unless otherwise specified, all percentages are by weight.
shows.

Example 1 400 y of 70% glycolic acid was put into a 500 me flask equipped with a stirrer, a thermometer, and a condenser, and while stirring, the glycolic acid was concentrated at a temperature of 160° C. and a degree of vacuum of 62 mm H9. After approximately 1,202 ml of water was distilled off, 0.280 y of primary chloride (SnC1r 2H,O) was added, the temperature and degree of vacuum were gradually increased, and the temperature and vacuum were gradually increased to 225°C.
[] Reaction was carried out for 8 hours with mmI-Ty. 8
After the reaction for hours, the molecular weight of gua 1 colide is 3000
At this time, 20.4y of liquid paraffin (729% based on glycolic acid) was added, and the temperature was 245°C and the degree of vacuum was 5.
The reaction was carried out at mmH9 for 10 hours.

After the reaction was completed, the molecular weight of the polycondensate was measured and found to be 9,800.

For comparison, the same reaction was carried out without adding the liquid paraffin, and the resulting polyglycolide had a molecular weight of 5,250.

Example 2 A flask similar to Example 1 contained 450 y of 90% L-lactic acid.
and while stirring, reduce the temperature to 165°C and reduce the pressure to 30°C.
L-lactic acid was concentrated with mmHy.

After about 45p of water has distilled out, stannous pyrophosphate (S
nr Pr O+ ) was added for 0.851y, the temperature and degree of vacuum were gradually increased by t, and the mixture was heated to
The reaction was carried out for ~26 hours.

When these operations were carried out in the same manner and the reaction was carried out for 2 to 26 hours, the molecular weights of the polycondensates were as shown in Table 1. 536%) was added thereto, and the reaction was carried out again at a temperature of 212° C. and a reduced pressure of 20 mm Hp for 19 hours.

After the reaction was completed, the molecular weight of each polycondensate was measured and the results are shown in Table 1.

Table 1 Example 6 I0 with N, gas inlet pipe, thermometer and condenser
0 me 90% L-lactic acid 60y in a glass reactor
and 0.059y of titanium tetrachloride (0°174% Ti aqueous solution) was added thereto.

The temperature was raised to 210° C. while blowing nitrogen gas into the reaction solution at a flow rate of 200 mel. temperature to 210
The molecular weight of the polycondensate reached 4000 after about 6 hours.
At the point when
dn, the reaction was carried out at a temperature of 205°C for 18 hours.

After the reaction was completed, the molecular weight of each polycondensate was measured and the results are shown in Table 2.

Table 2 Example 4 SSO equipped with N, gas inlet pipe, thermometer, and condenser
, 1 (<200y of 90% L-lactic acid in a glass reactor
and add stannous chloride (Bnalt・2HIO) to this.
) were added at o, oa+y.

The temperature was raised to 208° C. while blowing nitrogen gas into the reaction solution at a flow rate of 50,077 rpm. The temperature was maintained at 208°C, and when the molecular weight of the polycondensate reached 4,200 after about 9 hours, the additives shown in Table 3 were added, and the mixture was heated at 209°C with N and a gas flow rate of 950 me/win. A time reaction was performed.

After the reaction was completed, the molecular weight of each polycondensate was measured and the results are shown in Table 6.

Claims (3)

[Claims] (1) A method for producing polyglycolide or polylactide, which comprises using liquid paraffin during polycondensation. (2) The production method according to claim 1, wherein the proportion of liquid paraffin used is 5 to 30% by weight based on polyglycolide or polylactide. (3) The production method according to claim 1, wherein the addition of liquid paraffin is started when the molecular weight during polycondensation is 2,000 to 6,000.