It is a translation based on the content of corporate PR magazine“Sanyo Chemical News” issued in early spring 2019(No.512)

Useful performance chemicals by Sanyo Chemical Industries’ Group

Medical Use

Seiji Horie

Polyethylene Glycol
Medicines include those for(Mn). We have PEG products whose

Chief, Functional Materials Research Dept.
Biotechnology & Medical Division(1) Appearance and Properties

internal use, external use for skin and

Mn ranges between about 200 and

MACROGOL is liquid, paste or

mucous membranes, and direct

20,000. PEG products are liquid,

solid (flake or powder) depending on

injections into blood vessels.

paste or solid depending on thethe molecular weight (Fig. 3).

Depending on the use and purpose,molecular weight. They features are

Different grades of MACROGOL

there are various forms of medicines[1] low toxicity, [2] high lubricity, [3]each having different properties e.g.

including powder, tablets, cream andcapability of mixing with other PEG

vapor pressure (Table 2). They can beliquid. Compounds other than the

products of different molecular

mixed together to produce medicines

active pharmaceutical ingredients inweight and [4] high solubility withhaving desired hardness and viscosity.

medicines are called excipientswater and many types of organic(2) Solubility into solvent(additives). They are intentionallysolvent. Taking advantage of these

Table 3 shows solubility of

formulated in order to assure stability,

favorable features, they have been

MACROGOL. At low temperatures,

safety and uniformity depending on

used for various fields including

the higher molecular weight ofthe characteristics of the medicines.

medicines, medical excipients, hair

MACROGOL, it shows the lower

They play specific functional roles incare and skincare products, detergents,

solubility into polar solvents.

the facilitating dissolving or sustained

pigment dispersant, lubricant andHowever, at 50°C, a high solubility isrelease as required. Our polyethylene

binder.

obtained regardless of the molecular

We have six different types ofglycol (PEG) for medical use,
MACROGOL products are one of

medical use PEG products

pharmaceutical excipient.

MACROGOL as shown in Table 1.

Polyethylene Glycol
In 1960, our company developed,
first in Japan, PEG products. They
have been used for various uses.
Among many of our PEG products,
those used as medical ingredients or
excipients are called MACROGOL.
PEG is presented generally by themolecular formula as shown in Fig. 1.
It is a polymer and has a molecularweight distribution. A molecularweight distribution is defined by anumber-average molecular weight

They are listed by the JapanesePharmacopoeia or JapanesePharmaceutical Excipients. To ensure

Fig. 1 Molecular formula ofpolyethylene glycol

the safety and quality of the PEG
products, they are manufactured
under strict management system
which is complying with standard forGood Manufacturing Practice [GMP]
applicable for manufacturing andquality control in conformity with theself-imposed standard forpharmaceutical excipient GMP (Fig.
2).

Features of MACROGOL

Fig. 2 GMP-compliant plantweight. MACROGOL hardly solves
into nonpolar solvents even at hightemperatures.

Sanyo Chemical Industries’ News 1 early spring 2019, No. 512

with time for MACROGOL 1500. At
higher storage temperature, thechange proceeds faster. Therefore, toretard the change, they should be
stored in a cool, dark place.
MACROGOL 400

MACROGOL 1500

Liquid400

Paste

MACROGOL is hygroscopic. They

MACROGOL 6000
Solid (flake)

Solid (powder)should therefore be kept away fromLarge

moisture. MACROGOL of a larger

Smallmolecular weight shows a lower

Average molecular weighthygroscopicity.

Fig. 3 Appearance and average molecular weight of MACROGOLApplications of MACROGOL

Pharmaceutical Excipients,(3) Safety (toxicity)
MACROGOL has lower toxicity

MACROGOL’s pH value ranges(1) Pharmaceutical Excipients(in terms of LD50 [Acute Oralwidely between 4.0 and 7.0. This is

Toxicity]) (Table 4). MACROGOL

because polyether compounds such asof pharmaceutical excipientsof a larger molecular weight shows a

MACROGOL are subject to oxidative

including diluents and binders.1)

lower toxicity.
(4) Change over timedegradation. It is attributable to

The pharmaceutical excipients notoxygen radicals, which can lead tomerely are additives for making

decrease in pH value with time.

pharmaceutical preparation according

Figure 4 shows change of pH value

to the desired effects, but also

According to the JapanesePharmacopoeia or the Japanese

There are about 70 different kinds

Table 1 Physical-chemical characteristics of MACROGOL listed by the Japanese Pharmaceutical Excipients or the Japanese Pharmacopoeia
Product nameApplicable official
standard (list)

Form
Freezing point (°C)

MACROGOL 200

MACROGOL 400

MACROGOL 1500

MACROGOL 4000

MACROGOL
6000

MACROGOL 20000

Japanese
Pharmaceutical
ExcipientsJapanese
Pharmacopoeia

Japanese
Pharmacopoeia

Japanese
Pharmacopoeia

Japanese
Pharmacopoeia

Japanese
Pharmacopoeia

Colorless,transparent viscous
liquidColorless,transparent viscous
liquidPaste in white

Powder in white

Powder or flake inwhite

Powder in white-35 or below

6

40

55

58

60

Specific gravity(20/20°C)

1.120

1.120

-

-

-

-

pH*1

5.5

6

5.5

7

7

7

Mn

200

400

550

3,100

8,600

20,000

Water content (%)

1.0 or below

1.0 or below

1.0 or below

1.0 or below

1.0 or below

1.0 or below

Ignition residue (%)

0.10 or below

0.10 or below

0.10 or below

0.25 or below

0.25 or below

0.25 or below*2*3*1 Measured with a sample of 5 g diluted with 100 mL water *2 Mn average molecular weight calculated based on the hydroxyl value measured according to JIS
K1557 *3 Mixture of two different HOCH2(CH2OCH2)nCH2OH compounds whose “n” value is 5-6 and 28-36 respectively
The numbers that follow the word MACROGOL represent the average molecular weight. However, for MACROGOL 1500, 4000 and 6000 only, note that they do
not represent the average molecular weight.
To use or handle our products, contact our sales office. Before use, read through the latest version of the safety data sheet (SDS). Users shall be responsible fordetermining suitability and safety of the product that they will use in each individual application.
Table 2 Properties of MACROGOL
MACROGOL 200

MACROGOL 400

MACROGOL 1500

MACROGOL
4000

MACROGOL 6000

MACROGOL
20000

Mn*1

200

400

550*3

3,100

8,600

20,000Kinematic viscosity(mm2/s [210°F])

4.1

7.1

16

80

Product name

800

14000

Vapor pressure(Pa [100°C])

1.3

1.2×10-<2.7×10<2.7×10<2.7×10-10Specific heat(kJkg-1K-1)

2.2*2

2.2*2

2.3*3

2.3*3

2.3*3

2.5*3

-

150

160

180

190

190

44.5

44.5

-

-

-

-

Fusion heat (kJkg-1)
Surface tension(mN/m [25°C])

-2

-10

-10

*1 Mn average molecular weight calculated based on the hydroxyl value measured according to JIS K1557 *2 Average value at temperature between 30 and
60°C *3 Average value at temperature between the freezing point and 100°C
Table 3

Solubility of MACROGOL

Table 4 Toxicity of MACROGOL

Sanyo Chemical Industries’ News 2 early spring 2019, No. 512

LD50*1(g/kg [oral, rat])

Measuringtemperature

Water

Methanol

Ethanol

Diethyl ether

20°C

A

A

A

*1

D

MACROGOL 200

28

50°C

A

A

A

*1

D

MACROGOL 400

30

MACROGOL
1500

20°C

A

A

D

*2

D

MACROGOL 1500

44

50°C

A

A

A

*1

D

MACROGOL 4000

50

MACROGOL
4000

20°C

B

C

D

*2

D

MACROGOL 6000

50

50°C

A

A

A

*1

D

20°C

C

C

D

*2

D

Product name
MACROGOL 200

MACROGOL
20000*1 95% ethanol*2 99.5% ethanol
LegendA: Dissolve ≥100 g with a solvent of 100 mL
C: Dissolve 1 to <50 g with a solvent of 100 mL

lend [1] easy use (in handling andpH (5 mass% aqueous solution)(prevention of deterioration), [3]higher usefulness (helping theactive ingredient to reach thetarget area; adjusting the
manifestation of the medicinal
effect) and [4] higher safety (e.g.
reduction of side effects) to thedrug.
(2) Examples of applications
Features such as lower toxicity ,higher versatility and various formsof MACROGOL, make it useful as
medical additive for various
applications (Table 5).
MACROGOL in liquid can be used
as a moisturizer, stabilizer for
liquids for external use, andsolubilizing agent for lipophilic
drugs. It helps the drug permeating
into the affected part effectively.
MACROGOL in paste, Vaselinelike pasty material, can be used formaking an ointment of desired

Storagetemperature: 5°C

Storagetemperature: 25°C

Storagetemperature: 40°C

Storage started

Fig. 4* 1 Registry of Toxic Effects of Chemical substances,Feb. 2003 (NIOSH)

B: Dissolve 50 to <100 g with a solvent of 100 mL
D: Dissolve <1 g with a solvent of 100 mL

viscosity so that it can be spread
uniformly over the affected part.
MACROGOL in flake or powder,paraffin-like solid material, has amoldability, so that it can be used
for preparing suppositories. It canbe used also as a tablet coating
agent to increase the tablet’s surface
smoothness. It can harden thesurface of tablets to improve theirfriability and flowability. Among
many of MACROGOL application
areas, here describes its use as acolon cleansing agent andprecipitant for blood plasma
fractionation as well that has notbeen much introduced to date.
(3) Colon cleansing agent
Before inspection or surgery forcolorectal cancer or other colonicdiseases, bowel preparation forcolonic cleansing is necessary.
Inadequate bowel preparation canlead to poor colonic visualization,

taking the drug), [2] stable quality

Product nameElapse (month)

Change over time (MACROGOL 1500)

Since pH value measurements shown here may not be the case depending on the storage conditions of thesample, they should be used for reference only.
Sanyo Chemical Industries’ News 3 early spring 2019, No. 512

missed lesions, or other risks ofanastomotic failure or infectious
diseases. Intestinal lavage istherefore essential. Colon cleansing
agents are required to be [1] capableof facilitating quick, easy andefficient cleaning, [2] non-digestible
and non-absorbable, and capable ofpassing out through the bowel easily,and [3] minimal patient’s
discomfort (easy to take). PEG
formulation as colon cleansing
agent is osmotically balanced forthe kinds and concentration of theelectrolytes while acting as an agent
for retaining water in the bowel.
The water and electrolytes
concentrations in body fluids can be
kept well balanced. Feces can besoftened and discharged easily. PEG
is non-digestible and nonabsorbable so that it is directly
discharged out of the body.2) PEG
based agents do not induce
substantial shifts in fluid andelectrolyte level or poor patientcompliance, so that they have now
been used most widely among othertypes of colon cleansing agents.
(4) Precipitant for plasma
fractionation
An adult’s blood volume is about
80 mL per 1 kg of body weight.
Blood consists of cellularcomponents of erythrocyte,
leucocyte and platelet, and liquidpart called plasma. Cellularcomponents account for about 45%of the entire constituents of blood

Table 5 Application of MACROGOL
Use

Properties of medical drugs and additives

Base material for
ointment

Adjusts application concentration and viscosity of the ointment, keeps it applied uniformly over
the affected part, facilitates its sustainable permeation into the part, and absorbs body fluids
oozing out of the affected part.

Base material for
suppository

Mixing different MACROGOL products together will produce base materials having a desired
melting point and dissolution rate. MACROGOL of a higher average molecular weight shows ahigher storage stability.

Tablet binder

Available as a smoothing agent, coating agent or binder for manufacturing tablets. Comparedto sugar coating agents, it can shorten the coating time, and impart better aesthetics andharder surface to tablets.

It can be used also as a solvent, stabilizer, plasticizer, surfactant, lubricant, cohesive agent, luster, binder, smoothing
agent, moisturizer, emulsifier, pressure sensitive adhesive, adhesion enhancer, diluent, thickener, disintegrant,solubilizing agent, wetting agent, sugar coating agent, softener, wetting modifier, solubilizer, suspending agent,dispersant, desiccant and disintegrating agent, etc.

while the remainder is plasma.
Biological medicals produced
from blood e.g. donated blood are
generally called blood products.
They include blood component
products (erythrocyte, leucocyte andplatelet) intended for e.g. bloodtransfusion, and plasma derivatives.
They are produced by refining
proteins such as antibodies andblood clotting components.
MACROGOL can be used as aprecipitant when separating andrefining (fractionating) proteinsfrom blood.
Plasma consists of about 7 to 8%
of various types of proteins, about
90 to 91% of water, and theremainder of sugar and lipid.
Plasma derivatives are obtained byphysicochemically separating
Excluded volume
important proteins such as albumin
into individual components. Protein
Proteinis a condensation polymer
of 20

Osmoticpressure
Proteins associate and precipitate

Fig. 5 PEG acting as a precipitantfor plasma proteinskinds of amino acids. It has adifferent molecular characteristic
depending on the kinds andconfiguration of the composedamino acids. Moreover, plasma
proteins show complicatedmolecular characteristics because
they exist in the form of couples
with sugar (glucose) chains and/or
lipids (fats), Therefore, forfractionation (to separate and refine)plasma proteins, it is necessary toadjust processing parameters
depending on many factors such as
molecular characteristics, molecularweight and forms.
Fractionation processes include[1] PEG fractionation that uses PEG
as a precipitant for proteins, [2]ethanol fractionation that adjusts
five parameters of pH value, ionicstrength, ethanol concentration,
protein concentration andtemperature to change the solubilityof proteins, and [3] chromatography
fractionation.3)
PEG precipitates proteins by
reducing the dielectric constant andusing the excluded volume effect.
Figure 5 shows its working
mechanism. Osmotic pressuresexisting between the near-protein
region where PEG cannot enter andthe region in which PEG alreadyexists move proteins so that theycome closer to each other to achieve
thermal stabilization.4) Anotheradvantage of PEG is that it can
precipitate while minimizing themodification of protein molecules.
MACROGOL has been widely andeffectively used for manufacturing
medicines.

Prospects
Sanyo Chemical Industries’ News 4 early spring 2019, No. 512

At present, Japan has its own
official medicines lists of theJapanese Pharmacopoeia and theJapanese Pharmaceutical Excipients.
However, responding to
globalization of pharmaceuticalmanufacturing businesses, Japan,
America and EU countries arecooperating each other to develop aunified, international standard andlist of medicines. Our company will
enhance the PEG product lineups
ensuring that they comply with theinternational quality standard so that
we can globally contribute to thedevelopment of medicine.
Moreover, along the recent
advancement in medicines, we shallcontinue developing new, needoriented and high quality
pharmaceutical excipients.
References

1) IJEC Japan, ed. “Iyakuhin tenkabutu ziten 2000
(Dictionary of Pharmaceutical additives 2000), Yakuji
Nippo, Limited.
2)Davis GR, Ana SCA, Morawaski SG et al:
Gastroenterology 78; 991-995 (1980)
3)Hiroshi Morise “Kessyo bunkaku seizai-no seizou
houhou towa? (Wat is the method of manufacturing
plasma fractionation?), HP of Japan blood products
association (2018/11)
http://www.ketsukyo.or.jp/study/vol02_04.html.
4) Shunsuke Yoshizawa, Kentaro Shiraki “Seibutu
kogaku (Biotechnology)” vol.93, No.5 (2015), 260263[Contact (about the product)]

Sales & Marketing Dept., Biotechnology &Medical Division
http://www.sanyo-chemical.co.jp/eng/