Polyethylene

glycols (PEGs) and the

pharmaceutical industry

Manufacture

Polyethylene glycols, also called

macrogols in the European
pharmaceutical industry, are
manufactured by polymerization of
ethylene oxide (EO) with either water,
mono ethylene glycol or diethylene
glycol as starting material, under alkaline
catalysis (1,2). After the desired
molecular weight is reached (usually
checked by viscosity measurements as
in-process control) the reaction is
terminated by neutralizing the catalyst
with acid. Normally lactic acid is used,
but also acetic acid or others can be
found.
The result is a very simple chemical
structure: HO-[CH2-CH2-O]n-H, where (n)
is the number of EO-units.

Nomenclature

Although technically these products

should be called polyethylene oxides, for
products with mean molecular weights of
200 to 35,000, the term polyethylene
glycols is normally used to indicate the
significant influence of the hydroxyl end
groups on the chemical and physical
properties of these molecules. Only
products made by polymerization of
ethylene oxide in solvents with molecular
weights up to several millions are called
polyethylene oxides.
As an abbreviation for polyglycols, the
term PEG is used, in combination with
a numerical value. Within the
pharmaceutical industry, the number
indicates the mean molecular weight,
whereas in the cosmetic industry the
number refers to the number (n) of
EO-units in the molecule (3). Since the
molecular weight of ethylene oxide is 44,
FINE, SPECIALTY & PERFORMANCE CHEMICALS

the average molecular weight values of

the PEGs are given as round values of
n*44.
Unfortunately, the various
pharmacopeias use different nomenclature
for some PEG molecular weights. Table I
lists, in addition to the European, US and
Japanese monographs, also the
nomenclature of the British Pharmacopeia II
from 1993. Even if this monograph is no
longer valid, the nomenclature is still often
used today.
It is hoped that through the
international harmonization of the
pharmacopeias (8) a unique and less
confusing nomenclature will be developed.

TORSTEN HENNING
Clariant GmbH
65926 Frankfurt, Germany

Properties

Polyethylene glycols with a mean

molecular weight up to 400 are nonvolatile liquids at room temperature.
PEG 600 shows a melting range of about
17 to 22C, so it may be liquid at room
temperature but pasty at lower
environmental temperatures, while PEGs
with 800 to 2000 mean molecular
weight are pasty materials with a low
melting range. Above a molecular weight
of 3000, the polyethylene glycols are
solids and are available not only in flaked
form but also as powder. Polyglycols up
to a molecular weight of 35,000 are
commercially available. The hardness of
polyglycols increases with increasing
molecular weight, however the melting
range goes up to a maximum value of
about 60C (9).
The most important property of all
PEGs is their solubility in water, which
makes them ideally suitable for use in
countless different applications. Liquid
PEGs up to PEG 600 are miscible with
water in any ratio. But even solid PEG
grades have excellent solubility in water.
Although it falls slightly with increasing

Polyethylene glycols are a product

group with a wide range of
applications both in the industrial
chemical and pharmaceutical
industries. The manufacture,
nomenclature, physical-chemical
properties and toxicology of
polyethylene glycols are
summarized. The different
application fields of polyethylene
glycols are shown.

ABSTRACT

INTRODUCTION

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& PERFORMANCE
CHEMICALS

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molar mass, even 50% (w/w) of a PEG

35,000 can be dissolved at room
temperature in water. The solubility and
the viscosity of the solutions are not
affected by the presence of electrolytes,
since PEGs are nonionic substances. PEGs
are quite soluble in hard water or in other
aqueous solutions of various salts.
Some substances react with PEGs by
forming precipitates, for instance phenol,
cresol, resorcinol, salicylic acid, tannin,
potassium iodide, tetraiodo-bismutic acid
or mercury chloride beside others. Some
of those reactions can be used for
qualitative detection or quantitatively
analysis of polyethylene glycols. In
addition liquid PEGs can be used as
antidotes to remove some of the above
mentioned toxic substances from burned
skin.
Another very important property is the
solvent power for numerous substances
that are sparingly soluble in water. This
action can be ascribed to the formation of
a sort of complex between the
polyethylene glycol and the active
substance. Most of those complexes are
loose and reversible, there are only some
examples where the complexes tend to
inactivate the active substance, well
known are penicillin G and W and
Bacitracine (10) or acetylsalicylic
acid (11).
The polyethylene glycols show
outstanding toxicological safety regarding
acute and chronic oral toxicity,
embryotoxicity or skin compatibility
(12-14), supported by parenteral /
absorption / excretion investigations
(15-19). Therefore they have been used
for many years in cosmetics, foodstuffs
(20) and the pharmaceutical industry and
are registered in all relevant
pharmacopeias. The acceptable daily
intake (ADI-value) for polyethylene glycols
in foodstuffs is defined by the World
Health Organization (WHO) as a
maximum of 10 mg/kg body weight (21).

APPLICATIONS
PEGs as Excipients
Liquids
The very good solvent
power leads to a broad use
of low molecular weight
PEGs 200 to 400 in liquid
preparations as there are
drops, parenterals or fillings
for gelatin capsules.
Polyethylene glycol does not
soften gelatin.
The liquid PEGs have a
slightly bitter taste, but can
be adjusted easily by suitable
additives (sweeteners). Solid
PEG grades show a neutral
taste.

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Ointment Bases
It is very interesting that solid PEGs are not
soluble in liquid polyethylene glycols.
Blending pasty or solid PEGs together with
liquid PEGs will lead to a white, pasty
ointment with good solubility in water, good
dissolving properties and suitable for many
active substances.
The three most common PEG ointment
mixtures are:
40% Polyglykol 3350 +
60% Polyglykol 400 (22),
50% Polyglykol 4000 (Japanese name
for Polyglykol 3350) + 50% Polyglykol
400 (23),
50% Polyglykol 1500 +
50% Polyglykol 300 (24), offered
for example as Lanogen 1500.
Suppositories

Solid polyglycols are preferred bases as

suppository masses. Numerous actives can
be dissolved in PEGs and have then a good
bioavailability (25,26). The dissipation of
the active takes place not only by melting
within the body but also by dissolving in
the body fluids.
During the manufacturing they show
easy release from the mold, high stability
and no refrigeration is required (27) during
storage. The desired solidity can be adjusted
by choosing the molecular weight and
suitable ratios. For example 25% PEG 1000
and 75% PEG 1500 give very soft masses,
25% PEG 4000 S and 75% PEG 6000 S
will give more solid products (28).
Tablets
The manufacture of tablets requires
numerous excipients with different
functions, several of them covered by PEGs.
Polyglycols may be carriers, solubilizers and
absorption improvers for active substances,
usually processed in the form of a melt
(melt granulation), of course restricted to
cases where the active substances
withstand heating to about 70C.
They also act as lubricants and binders
(29) during the tablet processing. The
relatively low melting point favors a
sintering or compression technique. At the
same time the PEG has a plasticizing effect
which facilitates the shaping of the tablet
mass in the compression process and may
counteract capping.

Solid PEGs are also frequently used in

tablet coatings. The flexibility of sugarcoated tablets is increased by PEGs and
since polyethylene glycol acts as a
anticaking agent, the cores are prevented
from sticking together. With usually used
film formers in sugar-free coatings PEG acts
as softener.

PEGs as Actives
Ophthalmic Demulcents
Polyethylene glycol 300 and 400 are listed
as active ingredients in ophthalmic
demulcents in amounts of 0.2 to 1% (30).
Polyethylene glycols are treated as one
class of compounds, also reflected by the
use of one single CAS-number for the
whole class of polyethylene glycols, it is
likely that higher molecular weight PEGs
show similar properties for this application.
Thus polyethylene glycol 6000 is listed as
an ophthalmic demulcent active
ingredient (31).
Laxatives

Since polyethylene glycol is both highly

water soluble and not absorbed by
humans (32), it is superior to solutions
of other difficult to absorb materials with
an osmotic mode of action, such as e.g.
mannitol. PEGs cause fewer side effects
such as nausea or gas formation (33).
Since up to now there is no review article
available dealing with the osmotic activity
of PEGs, only some examples from the
literature are cited here in the
appendix (34-36).
The USP/NF describes a blend in the
monograph PEG 3350 and Electrolytes for
Oral Solution which contains a detailed
description of all potential individual salt
components to be used in addition to the
polyglycol with a mean molecular weight of
3350 (37). The existence of this
monograph explains why the mean
molecular weight of 3350 is used so
frequently in laxative preparations, although
PEGs with other molecular weights would
have an essentially equivalent effect. The
confusing nomenclatures (see Table I)
also contribute to the use of the type 3350,
since this type is registered in Japan
(under the name 4000) (38).

Table I - Different nomenclatures for PEGs

Mean
Molecular
Weight

Clariant
Polyglykol

Nomenclature
European Ph.
2001 (4)

Nomenclature
USP
24/NF 19 (5)

Nomenclature
Japanese
Ph. XIII (6)

Nomenclature
British Ph. II (7)

1500
3000
3350
4000
6000
8000
Ointment base
300 : 1500 = 1 : 1

1500 S
3000 S or P
3350 S or P
4000 S or P
6000 S or P
8000 S or P
Lanogen
1500

1500
3000
3350
4000
6000
8000
-

1500
3000
3350
4000
6000
8000
-

4000
6000
1500

1540
4000
-

FINE, SPECIALTY & PERFORMANCE CHEMICALS

Organ Preservation
A very specific and interesting application
is the use of linear high molecular weight
polyethylene glycol (20,000 daltons) in
compositions that exhibit antiapoptotic
activity that can be used therefore to
protect, preserve or restore cell, tissue or
organ function (39). In this application the
polyethylene glycol must be seen as the
active ingredient. The full explanation, why
PEG show the antiapoptotic activity and
why longer chains are more efficient than
short ones is missing yet. Collins (40)
suggests that the higher molecular weight
PEG has a direct tolerogenic action on
donor antigen in the transplanted organ. He
assumes that some sort of attachment of
PEG to transplantation antigens must have
occurred, without chemical combination,
but this is not proved. An earlier explanation
from Daniel (41) is that an essential
component of the medium is a non toxic
solute which does not cross the cell
membrane a low temperatures and could
therefore counterbalance the osmotic effect
of the intracellular proteins.

overview over the properties of

polyethylene glycols which are relevant for
their use in pharmaceutical applications and
to show the advantages. A broad literature
survey is given as starting points for those
who want to go in more detail for the
application work.

REFERENCES
1)

2)

3)

4)
5)

PEGs as Reaction Compounds

for Drug Delivery Systems

6)

With the two OH groups at the ends of

7)

the polyethylene glycol molecules, all

reactions typical for alcohols are possible,
first of all esters buildings among others as
carbonates and carbamates formation. To
avoid chain-building reactions methylethercapped PEGs, so called Methylpolyethylene
glycols, are available. Those MPEGs are
only able to react at one end of the
molecule.
The wide field of PEG conjugation to
proteins and other organic molecules, e.g.
anticancer drugs, would overcome the
limited aim of this article. Harris (42) as
well as later Greenwald (43) took carefully
together overviews over the so called
PEGnology. A first easy to read and shorter
introduction might be for example the
summaries of Bonora(44) or
Veronese (45).
Concerning anticancer drugs,
polyethylene glycol may work also without
linked to other molecules in some cases. In
one animal test, polyglycol was found to
prevent colon cancer (46), which should
also prove true in humans (47,48).

8)

9)
10)
11)
12)

13)
14)

15)
16)
17)
18)

SUMMARY

19)

The aim of this article is to give an

20)

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Macrogol / Polyethylene Gylcol 400 to 20000;
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SHAFFER, C.B. et al. J. Am. Pharm. Assoc.
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Polyethylene glycol, 21 CFR 172.820, FDA

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the Joint FAO/WHO Expert Comittee on Food
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648, 17-18
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USP 24/NF 19, Jan. 1, 2000, p.2495
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Ointment); The Japanese Pharmacopoeia,
XIII, 1996, p.826
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