POLYETHYLENE GLYCOLS
Prepared at the 31st JECFA (1987), published in FNP 38 (1988) and in
FNP 52 (1992). Metals and arsenic specifications revised at the 61st
JECFA (2003). An ADI of 0-10 mg/kg bw was established at the 23rd
JECFA (1979)
SYNONYMS PEG, Macrogol; INS No. 1521
DEFINITION Addition polymers of ethylene oxide and water usually designated by a
number roughly corresponding to the molecular weight.
Chemical names alpha-Hydro-omega-hydroxypoly (oxy-1,2-ethanediol)
C.A.S. number 25322-68-3
Chemical formula (C2H4O)n+1H2O
Structural formula HOCH2 - (CH2 - O - CH2)n - CH2OH
Formula weight 200-9500
DESCRIPTION PEG's below 700 molecular weight occur as clear to slightly hazy,
colourless, slightly hygroscopic liquids with a slight characteristic odour.
PEG's between 700-900 are semi-solid. PEG's over 1000 molecular weight
are creamy white waxy solids, flakes, or free-flowing powders.
FUNCTIONAL USES Carrier solvent, excipient
CHARACTERISTICS
IDENTIFICATION
Solubility (Vol. 4)
Polyethylene glycols having a molecular weight of 1000 or above are freely
soluble in water; polyethylene glycols are soluble in many organic solvents,
including aliphatic ketones and alcohols, chloroform, glycol ethers, esters,
and aromatic hydrocarbons; they are insoluble in ether and in most
aliphatic hydrocarbons; with increased molecular weight, water solubility
and solubility in organic solvents decrease
Molecular weight PEG's having molecular weight below 1000: not less than 95.0% and not
more than 105.0% of the declared value
PEG's having molecular weight between 1000 and 7000: not less than
90.0% and not more than 110.0% of the declared value
PEG's having molecular weight above 7000: not less than 87.5% and not
more than 112.5% of the declared value
See description under TESTS
Viscosity The viscosity ranges at 100±0.3o, in cSt for PEG's of various molecular
weight should be:
Average MW Viscosity range, cSt
200 4.1-4.8
300 5.4-6.4
400 6.8-8.0
500 8.3-9.6
600 9.9-11.3
700 11.5-13.0
800 12.5-14.5
900 15.0-17.0
1000 16.0-19.0
1100 18.0-22.0
1200 20.0-24.5
1300 22.0-27.0
1400 24.0-30.0
1450 25.0-32.0
1500 26.0-33.0
1600 28.0-36.0
1700 31.0-39.0
1800 33.0-42.0
1900 35.0-45.0
2000 38.0-49.0
2100 40.0-53.0
2200 43.0-56.0
2300 46.0-60.0
2400 49-65
2500 51-70
2600 54-74
2700 57-78
2800 60-83
2900 64-88
3000 67-93
3250 73-105
3350 76-110
3500 87-123
3750 99-140
4000 110-158
4250 123-177
4500 140-200
4750 150-228
5000 170-250
5500 206-315
6000 250-390
6500 295-480
7000 350-590
7500 405-735
8000 470-900
For PEG's not listed in the table, calculate the limits by interpolation. See
description under TESTS
PURITY
pH (Vol. 4)
4.5 - 7.5 (1 in 20 soln)
Sulfated ash (Vol. 4)
Not more than 0.1% w/w
Test 5 g of the sample
Acidity Not more than 0.05% w/w (as acetic acid)
Transfer 6 g of the sample into a 250-ml Erlenmeyer flask, add
phenolphthalein TS and 50 ml neutral ethanol and titrate with 0.1 N
ethanolic potassium hydroxide to a pink end-point that persists for at least
15 sec. Not more than 0.5 ml is required.
1,4-Dioxane Not more than 10 mg/kg.
Proceed as directed in the Limit Test using Gas chromatography. See also
Headspace gas chromatography method described below under the test
method for Ethylene oxide.
Ethylene oxide Not more than 0.02%
See description under TESTS
Ethylene glycol and
diethylene glycol
Total not more than 0.25% w/w individually or in combination
See description under TESTS
Lead (Vol. 4) Not more than 1 mg/kg
Determine using an atomic absorption technique appropriate to the
specified level. The selection of sample size and method of sample
preparation may be based on the principles of the method described in
Volume 4, “Instrumental Methods.”
TESTS
IDENTIFICATION TESTS
Molecular weight Phthalic anhydride solution
Place 49 g of phthalic anhydride in an amber bottle and dissolve it in 300
ml of pyridine that has been freshly distilled over phthalic anhydride. Shake
the bottle vigorously until solution is effected, and allow to stand overnight
before using.
Sample preparation for liquid polyethylene glycols
Carefully introduce 25 ml of the Phthalic anhydride solution into a clean,
dry, heat-resistant pressure bottle. To the bottle add an accurately weighed
amount of the sample equivalent to its expected molecular weight divided
by 160. (Thus, a sample of about 1.3 g would be taken for PEG 200, or
about 3.8 g for PEG 600). Stopper the bottle, and wrap it securely in a
fabric bag.
Sample preparation for solid polyethylene glycols
Carefully introduce 25 ml of the Phthalic anhydride solution into a clean,
dry, heat-resistant pressure bottle. To the bottle add an accurately weighed
amount of the sample, previously melted, equivalent to its expected
molecular weight divided by 160; because of limited solubility, however, do
not use more than 25 g of any sample. Add 25 ml of pyridine, freshly
distilled over phthalic anhydride, swirl to effect solution, stopper the bottle,
and wrap it securely in a fabric bag.
Procedure
Immerse the sample bottle in a water bath, maintained between 96o and
100o, to the same depth as that of the mixture in the bottle. Heat it in the
water bath for 30 to 60 min., then remove the bottle from the bath and
allow it to cool to room temperature. Uncap the bottle carefully to release
any pressure, remove the bottle from the fabric bag, add 5 drops of a 1 in
100 solution of phenolphthalein in pyridine, and titrate with 0.5 N sodium
hydroxide to the first pink colour that persists for 15 sec, recording the
volume, in ml of 0.5 N sodium hydroxide required as S. Perform a blank
determination on 25 ml of the Phthalic anhydride solution plus any
additional pyridine added to the sample bottle, and record the volume, in
ml of 0.5 N sodium hydroxide required as B. Calculate the molecular
weight of the sample by the formula:
where
W = weight of the sample in g
B = volume of 0.5 N NaOH consumed by the blank, in ml
S = volume of 0.5 N NaOH consumed by the sample, in ml
N = exact normality of NaOH
Alternative Tentative method using size exclusion chromatography (gel
permeation chromatography)
1. Polyethylene glycols having nominal molecular weight below 1000
Apparatus
Use a suitable HPLC chromatograph equipped with a differential
refractometer fitted with a 0.60 m x 7.7 mm (inside diameter) column
packed with PL gel 10 µm 50 Å with tetrahydrofuran as the mobile phase.
Operating Conditions
The operating parameters may vary depending upon the particular
instrument used but a suitable chromatogram may be obtained using the
following conditions:
-Mobile phase flow rate: 1 ml/min
- Pressure: 35 bars
- Injected volume: 20 µl of a 1% (w/v) solution
- Temperature of detection: 25o ± 0.1o
The procedure allows the identification of PEG by comparison with a
standard and to examine mixtures of PEG.
2. Polyethylene glycols having a nominal molecular weight of 1000 and
higher
The determination is carried out with the same procedure but with a mobile
phase: Tetrahydrofuran/n-heptane (80/20).
The elution volumes of PEG are approximately as follows depending on
the particular instrument and operating conditions.
Molecular Mass Elution Volume ml
35 000 21.2
10 000 22.8
6 000 24.2
4 000 25.1
2 000 26.8
1 000 28.4
Viscosity Apparatus
The Ubbelohde suspended level viscometer, shown in the Figure is
efficient for the determination of viscosity in the case of polyethylene
glycols. This apparatus is preferred for the determination of viscosity.
For use in the range of 300 to 600 centistrokes, a number 3 size
viscometer, having a capillary diameter of 2.00±0.04 mm, is required. The
viscometer should be fitted with holders which satisfy the dimensional
positions of the separate tubes as shown in the diagram, and which hold
the viscometer vertical. Filling lines in bulb A indicate the minimum and
maximum volumes of liquid to be used for convenient operation. The
volume of bulb B is approximately 5 ml.
Calibration of the Viscometer
Determine the viscosity constant (C) for each viscometer by using an oil of
known viscosity. Charge the viscometer by tilting the instrument about 30
degrees from the vertical, with bulb A below the capillary, and then
introduce enough of the sample into tube 1 to bring the level up to the
lower filling line. The level should not be above the upper filling line when
the viscometer is returned to the vertical position and the sample has
drained from tube 1. Charge the viscometer in such a manner that the U-
tube at the bottom fills completely without trapping air. After the viscometer
has been in a constant temperature bath long enough for the sample to
reach temperature equilibrium, place a finger over tube 3 and apply suction
to tube 2 until the liquid reaches the center of bulb C. Remove suction from
tube 2, then remove the finger from tube 3 and place it over tube 2 until the
sample drops away from the lower end of the capillary. Remove the finger
from tube 2, and measure the time, to the nearest 0.1 sec., required for the
meniscus to pass from the first timing mark (T1) to the second (T2). In order
to obtain accurate results within a reasonable time, the apparatus should
be adjusted to give an elapsed time of from 80 to 100 sec.
Calculate the viscometer constant C by the equation C = cSt/t1 in which cSt
is the viscosity, in centistokes, and t1 is the efflux time, in sec, for the
standard liquid.
Determine the viscosity of the sample, maintaining the constant
temperature bath at 100±0.3o and using a capillary viscometer having a
flow time of at least 200 sec for the PEG being tested. The viscosity must
be within the limits specified in the table, or interpolated from the table.
Figure. Ubbelhohde Viscometer (all dimensions are in mm)
PURITY TESTS
Ethylene oxide Morpholine solution
Mix one part of redistilled morpholine with nine parts of anhydrous
methanol.
Mixed indicator
Weigh 0.050 g of 4,4'bis-(amino-1-naphthylazo-2,2'-stilbenedisulfonic acid)
and 0.010 g of brilliant yellow into a 60-ml vial. Pipet 1.5 ml of 0.1 N
sodium hydroxide into the vial, and mix. Add 3.5 ml of water, and mix.
Transfer the mixture to a storage bottle with the aid of 45 ml of methanol as
a rinse, and mix.
Standard methanolic hydrochloric acid
Mix 8.5 ml of hydrochloric acid and 1000 ml of anhydrous methanol, and
standardize by titrating 9.00 ml with 0.1 N sodium hydroxide TS to a
phenolphthalein end-point. Restandardize if this solution is used more than
48 h after standardization.
Procedure
Place 50 ml of anhydrous methanol into a 250-ml conical flask. Add 4 to 6
drops of Mixed indicator, and titrate with Standard methanolic hydrochloric
acid to a clear blue colour.
Transfer to the flask about 25 g of the sample, accurately weighed, to
provide the specimen blank, swirl to effect complete solution. Titrate with
Standard methanolic hydrochloric acid to a clear blue colour, approaching
the end-point carefully using small increments of titrant. Place 50 ml of
Morpholine solution into a heat-resistant pressure bottle, and place an
equal amount into a similar bottle to provide the reagent blank. To the first
bottle add about 25 g of the sample, accurately weighed, and swirl to effect
complete solution. Wrap the bottles securely in a cloth bag, and place them
close together in a water bath maintained at 98±2o for 30 min, keeping the
water level in the bath just above the liquid level in the bottles. Remove the
bottles from the bath, and allow them to cool in air to room temperature.
When the bottles have cooled, loosen the wrappers, uncap to release any
pressure, and remove the wrappers. Slowly add 20 ml of acetic anhydride
to each bottle, and swirl to effect complete solution. Allow to stand at room
temperature for 15 min. If the bottles are still warm, cool them to room
temperature. To each bottle add 4 to 6 drops of Mixed indicator and titrate
with Standard methanolic hydrochloric acid to a clear blue colour, adding
very small increments when approaching the end-point.
Calculate the percentage of ethylene oxide by the formula:
where
N = the normality of the Standard methanolic hydrochloric acid
A, B, and C = the volumes (ml) required in the titration of the specimen, the
reagent blank, and the specimen blank, respectively
W1 and W2 = the weights (g) of the sample taken for the reaction and the
specimen blank, respectively
Headspace gas chromatography:
Alternative tentative method for 1,4-Dioxane and Ethylene oxide
Principle:
After addition of water to the sample, ethylene oxide and 1,4-dioxane are
analysed by headspace gas chromatography.
Standard Solutions
- 1,4-Dioxane Standard Stock Solution
Standard solutions of 1,4-dioxane in water are prepared by weighing out
about 1.00 g 1,4-dioxane/100 ml distilled water (stock solution) with
successive dilutions. Two standard solutions of about 20 and 100 µg 1,4-
dioxane/ml water are used.
- Ethylene Oxide (EO) Standard Stock Solution
In a 25 ml multidose injection vial, introduce 25 ml of distilled water. Close
the vial with septum and cap with a gas tight syringe. Introduce slowly into
the liquid 20 ml of ethylene oxide gas (about 40 mg). Determine the exact
amount of ethylene oxide added by weighing the vial before and after the
introduction of the gas (stock solution).
Prepare two working standard solutions by dilution with about 2 and 10 µg
ethylene oxide per ml of water by successive dilutions.
Apparatus
Use a suitable gas chromatograph equipped with a flame-ionization
detector (FID) containing a 30 m fused silica capillary column coated with
dimethylpolysiloxane, internal diameter 0.25 mm, film thickness 1.0 µm.
Operating Conditions
The operating conditions may vary depending upon the particular
instrument used, but the suitable chromatogram can be obtained using the
following conditions:
Headspace Sampler Setting
- Temperature equilibration time: 45 min
- Temperature: 70o
- Transfer line temperature: 150o
- Pressurization time: 30 sec
- Injection time: 6 sec
- Analysis time: 45 min
Gas chromatography conditions
- Temperature: Column, 50o (5 min isothermal), then 5o/min to 180o
Detector (FID), 250o
Carrier gas: Helium, 1 ml/min
Carrier pressure: 0.7 bar
Split ratio: 40 : 1
Hydrogen and air: for FID
Sample Preparations
Transfer about 1 g of the sample accurately weighed (± 0.1 mg) in a
headspace vial and add 1 ml of distilled water. Seal the vial and insert it
into the headspace analyser for equilibration 45 min at 70o.
Prepare in the same conditions 2 vials with each 1 g sample accurately
weighed (±0.1 mg) and 1 ml of standard stock solutions of 1,4-dioxane and
EO.
Standard Solutions for Work
Two standard solutions A and B (for spiking) are prepared as follows:
A. 1 ml EO stock solution with ca. 200 mg EO/100 ml + 2 ml 1,4-dioxane
stock solution with ca. 1000 mg dioxane/100 ml + water make up to 100
ml. This solution will be diluted 1 : 10 with water to yield a concentration of
about 2 µg EO/ml and 20 µg 1,4-dioxane/ml.
B. 1 ml EO stock solution with ca. 500 mg EO/100 ml + 5 ml 1.4 dioxane
stock solution with ca. 1000 mg dioxane/100 ml + water make up to 100
ml. This solution will be diluted 2 : 10 with water to yield a concentration of
about 10 µg EO/ml and 100 µg 1.4-dioxane/ml.
Calculation
The concentration of compound i can be calculated by the following
formula:
where
µg compound i/g = Mass portion of 1,4-dioxane or EO in the sample [µg/g]
Wi = Mass of spiked compound i normalized to 1 g sample [µg/g]
Ai = Peak area of compound i in the sample, normalized to 1 g sample
Ais = Peak area of compound i in the spiked sample, normalized to 1 g
sample
Ethylene glycol and
diethylene glycol
Polyethylene glycols having molecular weights below 450
Apparatus
Use a suitable gas chromatograph equipped with a hydrogen flame
ionization detector, containing a 1.5 m x 3 mm (inside diameter) stainless
steel column packed with sorbitol 12%, by weight, on 60/80 mesh non-
acid-washed diatomaceous earth (Chromosorb W, or equivalent).
Operating conditions
The operating parameters may vary, depending upon the particular
instrument used, but a suitable chromatogram may be obtained using the
following conditions: Column temperature: 165º; Inlet temperature: 260º;
Carrier gas: nitrogen (or suitable inert gas); flowing at a rate of 70 ml per
min; Recorder: -0.5 to 1.05 mv, full span, 1 sec. full response time;
Hydrogen and air flow to burner, optimize to give maximum sensitivity.
Standard solutions
Prepare chromatographic standards by dissolving accurately weighed
amounts of commercial ethylene glycol and diethylene glycol, previously
purified by distillation if necessary, in water. Suitable concentrations range
from 1 to 6 mg of each glycol per ml.
Sample preparation
Transfer about 4 g of the sample, accurately weighed, into a 10-ml
volumetric flask, dilute to volume with water and mix.
Procedure
Inject a 2 µl portion of each of the Standard solutions into the
chromatograph, and obtain the chromatogram for each solution. Under the
stated conditions, the elution time is approximately 2 min for ethylene
glycol and 6.5 min for diethylene glycol. Measure the peak heights, and
record the values as follows:
A = height, in mm, of the ethylene glycol peak;
B = weight, in mg, of ethylene glycol per ml of the Standard solution;
C = height, in mm, of the diethylene glycol peak; and
D = weight, in mg, of diethylene glycol per ml of the Standard solution
Similarly, inject a 2 µl portion of the Sample preparation into the
chromatograph, and obtain the chromatogram, recording the height of the
ethylene glycol peak as E and that of the diethylene glycol peak as F.
Calculation
Calculate the percent of ethylene glycol in the sample by the formula: (E x
B) / A x sample weight in g.
Calculate the percent of diethylene glycol in the sample by the formula: (F
x D) / C x sample weight in g.
Polyethylene glycols having molecular weights of 450 or higher
Sample preparation
Dissolve 50 g of the sample in 75 ml of diphenyl ether in a 250-ml
distillation flask. Slowly distil at a pressure of 1-2 mm of mercury into a
receiver graduated to 100 ml in 1-ml subdivisions, until 25 ml of distillate
has been collected. Add 25 ml of water
本文档为【POLYETHYLENE GLYCOLS-聚乙二醇】,请使用软件OFFICE或WPS软件打开。作品中的文字与图均可以修改和编辑,
图片更改请在作品中右键图片并更换,文字修改请直接点击文字进行修改,也可以新增和删除文档中的内容。
该文档来自用户分享,如有侵权行为请发邮件ishare@vip.sina.com联系网站客服,我们会及时删除。
[版权声明] 本站所有资料为用户分享产生,若发现您的权利被侵害,请联系客服邮件isharekefu@iask.cn,我们尽快处理。
本作品所展示的图片、画像、字体、音乐的版权可能需版权方额外授权,请谨慎使用。
网站提供的党政主题相关内容(国旗、国徽、党徽..)目的在于配合国家政策宣传,仅限个人学习分享使用,禁止用于任何广告和商用目的。