Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-03-27
2003-09-16
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S619000, C568S621000
Reexamination Certificate
active
06620976
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a polyethylene glycol with low ethylene glycol and diethylene glycol contents which is to be used in fields with application to a living body such as the pharmaceutical field and the cosmetic industry, and a process for producing the same.
2. Description of the Related Art
Polyethylene oxide, which is a material generally obtained by polymerizing ethylene oxide, has inherent characteristics of being viscous, causing no irritation, being soluble in water and having lubricating properties. Owing to these characteristics, this compound has been widely used in water base paints, paper coatings, adhesives, printing inks, surfactants and the like.
Among all, polyethylene glycol serves as an important material in producing drugs and cosmetics in the fields with respect to a living body such as the pharmaceutical field and the cosmetic industry, since it has excellent solubility and compatibility. In particular, polyethylene glycol compounds called “Macrogols” having different molecular weights are listed as official drugs in the Pharmacopoeia of Japan and employed as dissolution aids and fillers in various drugs and cosmetic materials.
Polyethylene glycol contains ethylene glycol and diethylene glycol the contents of which are specified to 0.25% (2,500 ppm) or less in the United States Pharmacopoeia etc., with respect to polyethylene glycols having a molecular weight of 1,000 or less for use in fields with application to a living body.
Among all, there has been no polyethylene glycol having an average molecular weight of from 190 to 210 which meets the requirement for ethylene glycol and diethylene glycol content as defined in United States Pharmacopoeia and the Pharmacopoeia of Japan, i.e., 0.25% (2,500 ppm) or less [J P Forum; Vol. 8, No. 4, 291-297 (1999)]. Although some polyethylene glycol products having an average molecular weight of 211 to 420 meet this standard, there is a requirement in fields concerning the living body such as the drug and cosmetic fields to further lessen the ethylene glycol and diethylene glycol contents.
With respect to polyethylene glycol having an average molecular weight of from 421 to 1,050, even commercial products meet the standards of the ethylene glycol and diethylene glycol contents stated in the United States Pharmacopoeia, i.e., 0.25% (2,500 ppm) or less. In fields concerning the living body such as the drug and cosmetic fields, however, there is a requirement to further lessen the ethylene glycol and diethylene glycol contents.
It has been a common practice to produce polyethylene glycol 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 with heating under elevated pressure. In this process, the remaining ethylene glycol or diethylene glycol decreases with an increase in the average molecular weight of the polyethylene glycol. In the case of polyethylene glycol having a relatively low molecular weight of from 190 to 420, the starting ethylene glycol or diethylene glycol tends to remain in large amounts.
In the case of polyethylene glycol having an average molecular weight of from 421 to 1,050, the ethylene glycol or diethylene glycol remains in a small amount compared with polyethylene glycol having an average molecular weight of from 190 to 420. However, ethylene glycol or diethylene glycol still remains in an amount exceeding the level required in the market.
Since these materials contain water, ethylene oxide is addition-polymerized with water so as to form ethylene glycol and diethylene glycol.
To remove ethylene glycol and diethylene glycol remaining in polyethylene glycol, use may be made of a method wherein low-boiling ethylene glycol and diethylene glycol are removed while bubbling nitrogen at a high temperature under reduced pressure. However, this method suffers from a problem in that when the contents of ethylene glycol and diethylene glycol are reduced to the level indicated by the following formula [I], the yield is largely lowered and deterioration arises due to excessive heating.
Sum
of
ethylene
glycol
and
diethylene
glycol
contents
(
ppm
)
=
150
×
2900
×
0.85
(
x
-
150
)
/
44
x
[
I
]
wherein x represents the average molecular weight of the polyethylene glycol.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a polyethylene glycol having an average molecular weight of from 190 to 1,050 for use in fields with application to a living body, wherein the sum of the contents of ethylene glycol and diethylene glycol is extremely low, and a process for producing the same.
The above object of the present invention has been achieved by providing:
(1) polyethylene glycol for use in fields with application to a living body, wherein the sum of the contents of ethylene glycol and diethylene glycol in the polyethylene glycol is less than or equal to that expressed by the following formula [I]:
Sum
of
ethylene
glycol
and
diethylene
glycol
contents
(
ppm
)
=
150
×
2900
×
0.85
(
x
-
150
)
/
44
x
[
I
]
wherein x represents the average molecular weight of the polyethylene glycol and the polyethylene glycol has an average molecular weight ranging from 190 to 1,050; and
(2) polyethylene glycol having an average molecular weight of from 190 to 210 for use in fields with application to a living body, containing ethylene glycol and diethylene glycol in a total amount of 200 ppm or less.
The formula [I] above is a formula whereby the sum of the ethylene glycol and diethylene glycol contents in polyethylene glycol at each molecular weight is calculated.
The ethylene glycol and diethylene glycol contents at each molecular weight are appropriately selected depending on the requirements of an intended application. In case of use in fields with application to a living body, it is favorable from the viewpoint of toxicity that the sum of the ethylene glycol and diethylene glycol contents is 2,500 ppm or less at a molecular weight of 200. Since the sum of ethylene glycol and diethylene glycol contained in the material and the sum of ethylene glycol and diethylene glycol formed as by-products during the reaction decrease with an increase in the addition mole number of ethylene oxide, the sum of the ethylene glycol and diethylene glycol contents in the product amounts to a value calculated by multiplying by a definite decreasing ratio.
In the above formula, 150 represents the molecular weight of triethylene glycol and 2,900 represents a coefficient concerning the acceptable level of the ethylene glycol and diethylene glycol contents in the material.
(x-150)/44 means the addition mole number of ethylene oxide. In the case where the decreasing ratio of the sum of the ethylene glycol and diethylene glycol contents per mole of ethylene oxide added is referred to as 0.85, the upper limit of the sum of ethylene glycol and diethylene glycol contained per mole (x g) of polyethylene glycol is thus indicated.
For some purposes, yet lower ethylene glycol and diethylene glycol levels are required. In the case of polyethylene glycol having a low molecular weight of from 190 to 210, in particular, the sum of the ethylene glycol and diethylene glycol contents is desirably 200 ppm or less.
The present invention further provides a process for producing such a polyethylene glycol. More particularly, the present invention provides:
(3) a process for producing polyethylene glycol according to (1) or (2) above which comprises addition-polymerizing ethylene oxide to triethylene glycol; and
(4) the process for producing a polyethylene glycol according to (3) above, which comprises, before the addition polymerization with eth
Sakanoue Kenji
Sanchika Kouzoh
Yasukohchi Tohru
NOF Corporation
Price Elvis O.
Richter Johann
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