JP2003221353A - Polyethylene glycol and production method therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide polyethylene glycol of which the sum of ethylene glycol and diethylene glycol contents is low and which has a mol.wt. of 190-1,050 and is used in organism-related fields. <P>SOLUTION: The polyethylene glycol has an average mol.wt. of 190-1,050, has a sum of ethylene glycol and diethylene glycol contents represented by formula (I) (wherein (x) is the average mol.wt. of the polyethylene glycol) or lower, is used in organism-related fields, and is prepared by the addition polymerization of ethylene oxide to triethylene glycol. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to polyethylene glycol having a low content of ethylene glycol and diethylene glycol, which is used in biomedical fields such as pharmaceutical industry and cosmetic industry, and a method for producing the same.

[0002]

2. Description of the Related Art In general, polyethylene glycol is a substance obtained by polymerizing ethylene oxide, has a viscous property, is non-irritating, is soluble in water, and has a lubricating property. It is a compound widely used for paper coating, adhesives, printing inks, and other surfactants.

[0003] Among them, polyethylene glycol is excellent in solubility and compatibility with drugs, so that in the biomedical fields of pharmaceutical industry and cosmetics industry,
It is a compound that is an important raw material for the manufacture of pharmaceuticals and cosmetics. In particular, it is used as a Japanese Pharmacopoeia drug "Macrogol", as a dissolving agent for various drugs, an excipient, and a cosmetic raw material, depending on the difference in molecular weight. It is also a compound.

Polyethylene glycol contains ethylene glycol and diethylene glycol. Regarding polyethylene glycol having a molecular weight of 1,000 or less used in the bio-related fields, its content is 0.25% (USP). 2,500 ppm) or less.

Among them, especially the average molecular weight of 190 to 2
Regarding the polyethylene glycol of 10, the content of ethylene glycol and diethylene glycol is 0.25% (2, 2, which is regulated by the US Pharmacopeia and the Japanese Pharmacopoeia).
500 ppm) or less was not satisfied [JP Forum ,; Vol. 8, No. 4,291
-297 (1999)]. Also, the average molecular weight of 211 to 4
Some of the polyethylene glycols of 20 satisfy this standard, but in the bio-related fields such as pharmaceutical preparations and cosmetics, it has been required to further reduce the content of ethylene glycol and diethylene glycol. .

Regarding polyethylene glycol having an average molecular weight of 421 to 1,050, even if it is a general product, it is 0.25% (2,500 pp, which is a standard of the US Pharmacopeia).
m) The following requirements are satisfied, but in the biomedical fields such as pharmaceutical preparations and cosmetics, the content of ethylene glycol and diethylene glycol should be further reduced.

Generally, polyethylene glycol is produced by addition-polymerizing ethylene oxide to ethylene glycol or diethylene glycol in the presence of an alkali catalyst such as sodium hydroxide or potassium hydroxide under pressure and temperature. . At this time, as the average molecular weight of polyethylene glycol increases, the residual amount of ethylene glycol or diethylene glycol as a raw material decreases, but in the case of polyethylene glycol having a relatively small average molecular weight of 190 to 420, The remaining amount of the raw material ethylene glycol or diethylene glycol tends to increase.

Further, in the case of polyethylene glycol having an average molecular weight of 421 to 1,050, the residual amount of ethylene glycol or diethylene glycol as a raw material is smaller than that of polyethylene glycol having an average molecular weight of 190 to 420. However, the level is not so low as to satisfy the demands of the market. Further, these raw materials contain water, and ethylene glycol and diethylene glycol are produced by addition-polymerizing ethylene oxide with water.

As a method for removing ethylene glycol and diethylene glycol remaining in polyethylene glycol, there is a method of distilling off low-boiling point ethylene glycol and diethylene glycol while blowing nitrogen under high temperature and reduced pressure. When the content is reduced to the content or less as shown in the following formula [I], the yield becomes very poor, and there is a problem that it deteriorates due to excessive heating.

[0010]

[Equation 2]

(Where x is the average molecular weight of polyethylene glycol)

[0012]

Therefore, the present invention is
To provide a polyethylene glycol having an average molecular weight of 190 to 1,050, which has a very low combined content of ethylene glycol and diethylene glycol, and which can be used in a biological field, and a method for producing the same. It is an issue.

[0013]

Means for Solving the Problems In the present invention for solving the problems, (1) the combined content of ethylene glycol and diethylene glycol is represented by the following formula [I]:

[0014]

[Equation 3]

A polyethylene glycol having an average molecular weight of 190 to 1,050, which is equal to or less than the content represented by the formula (wherein x is the average molecular weight of polyethylene glycol) and which is used in the biological field,

(2) A polyethylene glycol used in the biological field, which has a total content of ethylene glycol and diethylene glycol of 200 ppm or less and an average molecular weight of 190 to 210.

The above formula [I] shown here is a formula for calculating the total amount of ethylene glycol and diethylene glycol contained in polyethylene glycol at each molecular weight. The lower limit of the total amount of ethylene glycol and diethylene glycol can be up to the detection limit (1 ppm) of the measurement method.

The content of ethylene glycol and diethylene glycol in each molecular weight is appropriately selected according to the requirements, but when used in the bio-related fields, it is preferably 2,500 ppm or less at a molecular weight of 200 in consideration of toxicity and the like. Since the total amount of ethylene glycol and diethylene glycol contained in the raw material and the total amount of ethylene glycol and diethylene glycol by-produced during the reaction decrease due to the increase in the number of moles of ethylene oxide added, the total amount of ethylene glycol and diethylene glycol contained in the product The total amount of diethylene glycol is a value multiplied by a fixed reduction rate.

Here, 150 represents the molecular weight of triethylene glycol, and 2,900 is a coefficient relating to the allowable value of the content of ethylene glycol and diethylene glycol contained in the raw material. Also, (x-150) / 44
Is the number of moles of ethylene oxide added, and when the reduction rate of the total amount of ethylene glycol and diethylene glycol for every 1 mole of ethylene oxide added is 0.85, ethylene glycol and ethylene glycol contained per mole (xg) of polyethylene glycol and An upper limit on the amount of diethylene glycol will be given.

The content of ethylene glycol and diethylene glycol is required to be even lower depending on the intended use, and particularly low molecular weight molecular weights of 190 to 21 are required.
For polyethylene glycol which is 0, the content of ethylene glycol and diethylene glycol is 20
0 ppm or less is preferable.

The present invention also provides a method for producing such polyethylene glycol, and specifically, (3) the addition of ethylene oxide to triethylene glycol is carried out, and the method according to the above (1) or (2) is described. The method for producing polyethylene glycol, and (4) before the addition polymerization of ethylene oxide
The method for producing polyethylene glycol according to the above (3), characterized in that the dehydration treatment is performed under the conditions of 150 ° C., 0 to 0.013 MPa, and 0.5 to 3 hours.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION The polyethylene glycol provided by the present invention has an average molecular weight in the range of 190 to 1,050, and the content of ethylene glycol and diethylene glycol is not more than the content represented by the formula [I]. Is a polyethylene glycol that can be used in the biological field.

The average molecular weight provided by the present invention is 19
Polyethylene glycol having a content of ethylene glycol and diethylene glycol in the range of 0 to 210 is not more than the content represented by the formula [I], and more preferably not more than 200 ppm. However, it is extremely useful in view of the fact that there are no products that satisfy the standards of the US Pharmacopeia and that there are great demands from the market.

[0024]

[Equation 4]

(In the formula, x is the average molecular weight of polyethylene glycol.)

The average molecular weight x of polyethylene glycol is THE UNITED STATES.
PHARMACOPEIA 24, THE NATI
ONAL FORMULARY 19, UNITED
STATES PHARMACOPEIAL CON
VENTION, INC. January 1,20
00 Polyethylene Glycol / Of
financial Monographs average
It is measured by the method described in the molecular weight.

The upper limit of each molecular weight calculated from the above formula [I] is 1,808 ppm for polyethylene glycol having a molecular weight of 200, 833 ppm for polyethylene glycol having a molecular weight of 300, and polyethylene glycol having a molecular weight of 400. There is 432 ppm, and for polyethylene glycol with a molecular weight of 600, 138 pp
In the case of polyethylene glycol having m and a molecular weight of 1,000, it is 19 ppm.

[0028] Preferably, polyethylene glycol having a molecular weight of 200 has a content of 200 ppm and a molecular weight of 300.
Polyethylene glycol of 150 ppm, polyethylene glycol of 400 molecular weight is 100 ppm
ppm is 50 ppm for polyethylene glycol having a molecular weight of 600 and 15 ppm for polyethylene glycol having a molecular weight of 1,000.

It is not preferable that the content of ethylene glycol and diethylene glycol exceeds the content represented by the above formula [I] since the proportion of impurities becomes high.

The polyethylene glycol used in the biological field provided by the present invention means a physiologically usable polyethylene glycol. Specifically, it is directly used for the human body in the biological field. It means that it can be used for pharmaceutical products, cosmetics, toiletry products, etc. For example, it can be used as a base material for pharmaceuticals such as injectable preparations, preparations for external use, preparations for oral administration and the like, solubilizers, emulsifiers, dispersants, excipients and lubricants. Also, toilet soap, shampoo, rinse, face wash,
It can be used as a body-cleaning agent for toothpaste, cosmetics such as lotion, lotion, foundation, perfume and lipstick.

The polyethylene glycol having a low content of ethylene glycol and diethylene glycol and having an average molecular weight of 190 to 1,050 provided by the present invention is present in the presence of an alkali catalyst such as sodium hydroxide or potassium hydroxide. It can be produced by addition-polymerizing ethylene oxide to triethylene glycol under pressure and heat.

The purity of triethylene glycol used in the production in this case is not particularly limited, but it is preferably 99.5% or more, more preferably 99.95% or more. . The triethylene glycol used can be purified by subjecting it to distillation or the like for purification.

The alkaline catalyst used in the present invention is a strong alkaline substance such as sodium hydroxide and potassium hydroxide, and the addition amount thereof is 0.005 to 1.0% by weight based on the charged amount of triethylene glycol. %, More preferably about 0.01 to 0.5% by weight.

In the production method provided by the present invention, the reaction temperature of the addition polymerization reaction of ethylene oxide is 80 to 2
The temperature is preferably 30 ° C., more preferably 120 to 180 ° C., and the reaction pressure is preferably 0 to 1 MPa, more preferably 0.2 to 0.6 MPa. The excess ratio of ethylene oxide used in the reaction is preferably 0.8 to 1.2, and more preferably 0.98 to 1.06. The excess ratio is the ratio of the amount used to the theoretical amount of ethylene oxide required to obtain polyethylene glycol of the target molecular weight.

Before carrying out the addition polymerization reaction of ethylene oxide with respect to triethylene glycol, triethylene glycol is heated to 70 to 150 ° C. in a reaction vessel and reduced to 0.5 to 3 under a reduced pressure of 0 to 0.013 MPa. It was possible to further suppress the by-product of ethylene glycol and diethylene glycol by removing the water derived from the raw materials and the catalyst while blowing nitrogen under the conditions of time.

The contents of ethylene glycol and diethylene glycol in this case can be measured by the following method. This method is based on JP Foru
m ,; Vol. 8, No. 4,291-297 (199
The measurement method is based on “International Proposal of Polyethylene Glycol (Stage 3)“ Limits of Ethylene Glycol and Diethylene Glycol ”” described in 9), and the measurement conditions are as follows.

<Conditions for measuring the contents of ethylene glycol and diethylene glycol> Preparation of internal standard solution: 100 mg of 1,4-butanediol
Was weighed accurately in a 100 mL volumetric flask and diluted to the marked line with distilled water. Preparation of standard solution: ethylene glycol, diethylene glycol and 1,4-butanediol 50 mg each
Each was precisely weighed into a 100 mL volumetric flask and diluted with distilled water. Preparation of sample solution: The sample to be measured is precisely weighed in an amount of 4 g in a 10 ml container, and 5 ml of an internal standard solution,
Distilled water (1 ml) was accurately added, and the mixture was stoppered and shaken well.

Measurement conditions: Gas chromatography measurement under the following conditions was performed. Column: WCOT FUSEDSILICA 30mm
× 0.53mm CPWAX52CB film thickness 1.0μm
(GL Science) Carrier gas: He (helium gas) Linear velocity: 40 cm / sec Split port flow rate: 100 ml / min Inlet port temperature: 250 ° C Detector temperature: 260 ° C Column temperature: 180 ° C → 10 ° C / min → 260 ℃
(22 minutes) Injection volume: 1 μl

Calculation method: From the peak areas obtained from the standard solution and each sample solution, the response coefficient F was calculated using the equation (1).
_N was calculated and ethylene glycol and diethylene glycol were quantified using the formula (2). F _N = (C _N r _SI ) / (C _SI r _SN ) (1) C _N : concentration of ethylene glycol or diethylene glycol in standard solution (μg / ml) r _SI : of internal standard substance obtained from standard solution Peak area C _SI : Concentration of internal standard substance in standard solution (μg / ml) r _SN : Peak area of ethylene glycol or diethylene glycol obtained from standard solution

Content [wt%] = (F _N C _I r _N ) / (2000 r _I W) (2) C _I : Concentration of internal standard substance in internal standard solution (μg / ml) r _N , r _I : Ethylene glycol or diethylene glycol obtained from the sample solution, the peak area W of the internal standard substance: Weight [g] of each target substance in the sample solution Content [ppm] = Content [wt%] x 10000 (3)

The polyethylene glycol obtained in the present invention can be subjected to a step of removing excess ethylene oxide under reduced pressure, a step of neutralizing the alkali catalyst with an acid such as phosphoric acid or hydrochloric acid, or a step of removing the alkali catalyst with an adsorbent. Further, an antioxidant such as dibutylhydroxyltoluene or tocopherol may be added depending on the application.

[0042]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1: 1,500 g of triethylene glycol having a purity of 99.95% and 0.88 g of potassium hydroxide
(0.059% by weight based on triethylene glycol)
Was charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and was heated at 110 ° C. and 0.006.
It was dehydrated for 1 hour under a reduced pressure of 7 MPa while blowing nitrogen. After that, reaction temperature 140 ° C, reaction pressure 0.4M
While maintaining Pa, 510 g of ethylene oxide (excess ratio: 1.02) was introduced, and the reaction was carried out with stirring.
After all the ethylene oxide was introduced, aging was carried out at 140 ° C for 1 hour and then at 100 ° C for 1.5 hours at 0.002 MPa.
The ethylene oxide was removed under reduced pressure. This is 85 ℃
After cooling to, phosphoric acid was added for neutralization, and filtration was performed to obtain the target product (1), which was polyethylene glycol having an average molecular weight of 202 (yield: 97%). When an odor test of the obtained target product was conducted, no odor of decomposition of polyethylene glycol was found.

Example 2: 1,500 g of triethylene glycol having a purity of 99.95% and 1.32 g of potassium hydroxide
(0.088% by weight based on triethylene glycol)
Was charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and was heated at 110 ° C. and 0.006.
It was dehydrated for 1 hour under a reduced pressure of 7 MPa while blowing nitrogen. After that, reaction temperature 140 ° C, reaction pressure 0.4M
While maintaining Pa, ethylene oxide 1,530g
(Excess ratio: 1.02) was introduced and the reaction was carried out with stirring. Thereafter, the same treatment as in Example 1 was conducted to obtain an average molecular weight of 30
The target product (2) which is polyethylene glycol of 6 was obtained (yield: 95%). When an odor test of the obtained target product was conducted, no odor of decomposition of polyethylene glycol was found.

Example 3: 1,500 g of triethylene glycol having a purity of 99.95% and 1.76 g of potassium hydroxide
(0.117% by weight based on triethylene glycol)
Was charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and was heated at 110 ° C. and 0.006.
It was dehydrated for 1 hour under a reduced pressure of 7 MPa while blowing nitrogen. After that, reaction temperature 140 ° C, reaction pressure 0.4M
2,550 g of ethylene oxide while maintaining Pa
(Excess ratio: 1.02) was introduced and the reaction was carried out with stirring. After that, the same operation as in Example 1 was performed to obtain a target product (3) which was polyethylene glycol having an average molecular weight of 406 (yield: 96%). When an odor test of the obtained target product was conducted, no odor of decomposition of polyethylene glycol was found.

Example 4: 1,500 g of triethylene glycol having a purity of 99.95% and 0.88 g of potassium hydroxide
(0.059% by weight based on triethylene glycol)
Was charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and while maintaining a reaction temperature of 140 ° C. and a reaction pressure of 0.4 MPa, 510 g of ethylene oxide (excess ratio: 1.02) was introduced, and the reaction was performed while stirring. I went. After that, the same operation as in Example 1 was performed to obtain a target product (4) which was polyethylene glycol having an average molecular weight of 197 (yield: 97%). When an odor test of the obtained target product was conducted, no odor of decomposition of polyethylene glycol was found.

Example 5: 900 g of triethylene glycol having a purity of 99.95% and 1.58 g of potassium hydroxide (0.176% by weight based on triethylene glycol) were equipped with a stirrer, a dropping device and a nitrogen bubbling line.
Charged to L autoclave, 110 ℃, 0.0067M
Dehydration was performed for 1 hour under a reduced pressure of Pa while blowing nitrogen. After that, the reaction temperature is 140 ° C., the reaction pressure is 0.4 MPa
While maintaining at 2, 2,754 g (excess ratio: 1.02) of ethylene oxide was introduced, and the reaction was carried out with stirring.
After that, the same operation as in Example 1 was performed to obtain an average molecular weight of 602.
The target product (5), which is polyethylene glycol, was obtained (yield: 95%). When an odor test of the obtained target product was conducted, no odor of decomposition of polyethylene glycol was found.

Comparative Example 1: Diethylene glycol 1,06
0 g, sodium hydroxide 0.88 g (0.083 wt% with respect to diethylene glycol) were charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, while maintaining a reaction temperature of 140 ° C. and a reaction pressure of 0.4 MPa, 959 g of ethylene oxide (excess ratio: 1.
02) was introduced and the reaction was carried out with stirring. After that, the same operation as in Example 1 was performed to obtain a target product (6), which was polyethylene glycol having an average molecular weight of 201 (yield: 96%).

Comparative Example 2: Diethylene glycol 1,06
0 g and 0.88 g of potassium hydroxide (0.083% by weight with respect to diethylene glycol) were charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and at 110 ° C. under a reduced pressure of 0.0067 MPa, 1 while blowing nitrogen. It was dehydrated for an hour. Then, while maintaining the reaction temperature at 140 ° C. and the reaction pressure at 0.4 MPa, 959 g of ethylene oxide (excess ratio: 1.02) was introduced,
The reaction was carried out with stirring. Thereafter, the same operation as in Example 1 was carried out to obtain the target product (7) which was polyethylene glycol having an average molecular weight of 198 (yield: 97%).

Comparative Example 3: 620 g of ethylene glycol,
0.88 g of potassium hydroxide (0.142 wt% with respect to ethylene glycol) was charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and ethylene oxide was maintained while maintaining a reaction temperature of 140 ° C. and a reaction pressure of 0.4 MPa. 1,408 g (excess ratio: 1.0
2) was introduced and the reaction was carried out with stirring. After that, the same operation as in Example 1 was performed to obtain a target product (8), which was polyethylene glycol having an average molecular weight of 205 (yield: 95%).

Comparative Example 4: 620 g of ethylene glycol,
0.88 g of potassium hydroxide (0.142 wt% with respect to ethylene glycol) was charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and 1
Dehydration was performed for 1 hour while blowing nitrogen at 10 ° C. under a reduced pressure of 0.0067 MPa. Then, the reaction temperature 140
While maintaining the reaction pressure at 0.4 MPa and the reaction pressure at 0.4 MPa, 1,408 g of ethylene oxide (excess ratio: 1.02) was introduced, and the reaction was carried out with stirring. Thereafter, the same operation as in Example 1 was carried out to obtain the target product (9) which was polyethylene glycol having an average molecular weight of 203 (yield: 94%).

Comparative Example 5: Diethylene glycol 1,06
0 g and 1.32 g of potassium hydroxide (0.125 wt% with respect to diethylene glycol) were charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, while maintaining a reaction temperature of 140 ° C. and a reaction pressure of 0.4 MPa, Ethylene oxide 1,979 g (excess ratio:
1.02) was introduced and the reaction was carried out with stirring. After that, the same operation as in Example 1 was performed to obtain a target product (10) which was polyethylene glycol having an average molecular weight of 312 (yield: 96%).

Comparative Example 6: Diethylene glycol 1,06
0 g, potassium hydroxide 1.76 g (0.166 wt% with respect to diethylene glycol) were charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, while maintaining a reaction temperature of 140 ° C. and a reaction pressure of 0.4 MPa, 2,999 g of ethylene oxide (excess ratio:
1.02) was introduced and the reaction was carried out with stirring. After that, the same operation as in Example 1 was performed to obtain a target product (11), which was polyethylene glycol having an average molecular weight of 412 (yield: 95%).

Comparative Example 7: Diethylene glycol 1,06
0 g and 1.76 g of potassium hydroxide (0.166% by weight with respect to diethylene glycol) were charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and were blown with nitrogen at 110 ° C. under reduced pressure of 0.0067 MPa to obtain 1 It was dehydrated for an hour. Then, while maintaining the reaction temperature at 140 ° C. and the reaction pressure at 0.4 MPa, 2999 g of ethylene oxide (excess ratio: 1.02) was introduced, and the reaction was performed while stirring. Thereafter, the same operation as in Example 1 was carried out to obtain a target product (12) which was polyethylene glycol having an average molecular weight of 409 (yield: 95
%).

Comparative Example 8: Diethylene glycol 848
g, 2.11 g of potassium hydroxide (0.249% by weight with respect to diethylene glycol) were charged into a 5 L autoclave equipped with a stirrer, a dropping device and a nitrogen bubbling line, and were blown with nitrogen at 110 ° C. under a reduced pressure of 0.0067 MPa to obtain 1 It was dehydrated for an hour. Then reaction temperature 1
While maintaining the reaction pressure at 0.4 MPa at 40 ° C., 4,031 g (excess ratio: 1.02) of ethylene oxide was introduced, and the reaction was carried out with stirring. After that, the same operation as in Example 1 was performed to obtain a target product (13), which was polyethylene glycol having an average molecular weight of 610 (yield: 94
%).

The contents of ethylene glycol and diethylene glycol in the target products obtained in Examples 1 to 5 and Comparative Examples 1 to 8 were measured, and the results are shown in Table 1. The content of ethylene glycol and diethylene glycol is measured according to the above <Conditions for measuring content of ethylene glycol and diethylene glycol>.
The odor test was carried out as follows.

Odor test: 1 ml of the obtained target product was placed in a beaker, and its odor was evaluated according to the following criteria. Odorless: No or almost no odor. Odor: There is an odor of polyethylene glycol decomposition.

[0058]

[Table 1] Table 1: Content of ethylene glycol and diethylene glycol

In the above table, Examples 1, 2, 3 and 5 have molecular weights of 190 to 210 and 285 to 31 respectively.
Polyethylene glycol having 5, 380 to 420 and 570 to 630, which is obtained by subjecting triethylene glycol as a raw material to a dehydration treatment in a reaction vessel before an addition polymerization reaction with ethylene oxide. Also,
Example 4 is a polyethylene glycol having a molecular weight of 190 to 210, which is made of triethylene glycol as a raw material and is not dehydrated before the addition polymerization reaction with ethylene oxide.

When triethylene glycol is used as a raw material, the content of ethylene glycol and diethylene glycol can be suppressed to the content shown in the above formula [I] or less by the addition polymerization reaction with ethylene oxide. Furthermore, regarding polyethylene glycol having a molecular weight of 190 to 210, the content of ethylene glycol and diethylene glycol is adjusted to 200 by performing dehydration treatment before the addition polymerization reaction with ethylene oxide.
It can be reduced to below ppm.

On the other hand, in Comparative Examples 1 and 2, the molecular weight was 1
A polyethylene glycol having 90-210,
It is a product obtained by subjecting diethylene glycol as a raw material to a dehydration treatment before the addition polymerization reaction with ethylene oxide (Comparative Example 2) and a product not subjected to dehydration treatment (Comparative Example 1).

In Comparative Examples 3 and 4, the molecular weight is 190 to
Polyethylene glycol having 210, which is obtained by subjecting ethylene glycol as a raw material to a dehydration treatment before the addition polymerization reaction with ethylene oxide (Comparative Example 4) and not dehydrating it (Comparative Example 3).

In Comparative Example 5, the molecular weight is 285.
Polyethylene glycol having .about.315, which is obtained by using diethylene glycol as a raw material and not subjected to dehydration treatment before the addition polymerization reaction with ethylene oxide.

Further, Comparative Examples 6 and 7 are polyethylene glycols having a molecular weight of 380 to 420, which were prepared by using diethylene glycol as a raw material and subjected to dehydration treatment prior to the addition polymerization reaction with ethylene oxide (comparative). Example 7) and those not performed (Comparative Example 6).

Further, in Comparative Example 8, the molecular weight is 57.
It is a polyethylene glycol having 0 to 630, which is obtained by using diethylene glycol as a raw material and performing dehydration treatment before the addition polymerization reaction with ethylene oxide.

As is clear from the results of these Comparative Examples, when polyethylene glycol was produced by addition polymerization reaction of ethylene oxide with diethylene glycol as a raw material, the contents of ethylene glycol and diethylene glycol were high. Further, when polyethylene glycol is produced from ethylene glycol as a raw material by an addition polymerization reaction with ethylene oxide, the contents of ethylene glycol and diethylene glycol are further increased. This tendency did not change even if dehydration treatment was performed before the addition polymerization reaction with ethylene oxide.

As can be seen from the above results, the polyethylene glycol provided by the present invention is produced by addition polymerization reaction with ethylene oxide using triethylene glycol as a raw material. It is possible to keep the content extremely low, and
By dehydrating the inside of the reaction vessel before the addition polymerization reaction with ethylene oxide, the contents of ethylene glycol and diethylene glycol can be further suppressed to a low level.

[0068]

As described above, in the present invention, the total content of ethylene glycol and diethylene glycol is not more than the content represented by the following formula [I], and the average molecular weight is 190 to 1,050. The present invention provides a polyethylene glycol that can be used in biomedical fields such as pharmaceutical preparations and cosmetics. Among them, particularly for polyethylene glycol having an average molecular weight of 190 to 210, the content of ethylene glycol and diethylene glycol in the pharmaceutical field is It is now possible to provide products that meet the standards specified by the Japanese Pharmacopoeia or the US Pharmacopoeia.

[0069]

[Equation 5]

(In the formula, x is the average molecular weight of polyethylene glycol.)

In view of the fact that there is no such polyethylene glycol in the current market, and there is a great demand from the market for these polyethylene glycols, the present invention meets that demand, and is industrially utilized in the biological field. The sex is extremely large.

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Claims (4)

[Claims] 1. The combined content of ethylene glycol and diethylene glycol has an average molecular weight of 190 to 1.0.
In the case of 50, the formula [I]: A polyethylene glycol used in the biological field, which is equal to or less than the content represented by the formula (wherein x is the average molecular weight of polyethylene glycol). 2. A polyethylene glycol having an average molecular weight of 190 to 210 and having a total content of ethylene glycol and diethylene glycol of 200 ppm or less, which is used in the biological field. 3. The method for producing polyethylene glycol according to claim 1, wherein ethylene oxide is addition-polymerized with triethylene glycol. 4. Before addition-polymerizing ethylene oxide, the temperature is 70 to 150 ° C. and 0 to 0.01 in a reaction vessel.
The method for producing polyethylene glycol according to claim 3, wherein the dehydration treatment is performed under conditions of 3 MPa and 0.5 to 3 hours.