Hydroxyethylcellulose
— impurities C, D, E, F : for each impurity, not more than
the area of the principal peak in the chromatogram
obtained with reference solution (b) (0.1 per cent),
— any other impurity : for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (b) (0.1 per cent),
— total: not more than twice the area of the principal peak
in the chromatogram obtained with reference solution (a)
(1.0 per cent) ; disregard the peak due to the bromide ion
which appears close to the peak due to the solvent,
— disregard limit : 0.5 times the area of the principal peak
in the chromatogram obtained with reference solution (b)
(0.05 per cent).
Loss on drying (2.2.32) : maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 100-105 °C.
Sulphated ash (2.4.14) : maximum 0.1 per cent, determined
on 1.0 g.
ASSAY
Dissolve 0.300 g in 10 ml of water R. Titrate with 0.1 M
silver nitrate. Determine the end-point potentiometrically
(2.2.20), using a silver indicator electrode and a silver-silver
chloride reference electrode.
1 ml of 0.1 M silver nitrate is equivalent to 37.03 mg
of C17H24BrNO3.
STORAGE
Protected from light.
IMPURITIES
Specified impurities (see note for information p. xxxvii) :
A, B, C, D, E, F.
A. (1R,3s,5S)-3-[[(2RS)-2-hydroxy-2-phenylacetyl]oxy]-
8,8-dimethyl-8-azoniabicyclo[3.2.1]oct-6-ene
(methyldehydrohomatropine),
B. homatropine,
C. R = H : (2RS)-2-hydroxy-2-phenylacetic acid (mandelic
acid),
F. R = CH3 : methyl (2RS)-2-hydroxy-2-phenylacetate (methyl Apparent viscosity (2.2.10) : 75 per cent to 140 per cent of
mandelate),
D. (1R,2R,4S,5S,7s)-7-[[(2S)-3-hydroxy-2-phenylpro-
panoyl]oxy]-9,9-dimethyl-3-oxa-9-azoniatricyc-
2,4
lo[3.3.1.0 ]nonane (methylhyoscine),
E. methylatropine.
4496 See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 4.
04/2004:0336
HYDROXYETHYLCELLULOSE
Hydroxyethylcellulosum
DEFINITION
Partly O-(2-hydroxyethylated) cellulose.
CHARACTERS
Appearance : white, yellowish-white or greyish-white powder
or granules.
Solubility : soluble in hot and cold water giving a colloidal
solution, practically insoluble in acetone, in alcohol and in
toluene.
IDENTIFICATION
A. Heat 10 ml of solution S (see Tests) to boiling. The
solution remains clear.
B. To 10 ml of solution S add 0.3 ml of dilute acetic acid R
and 2.5 ml of a 100 g/l solution of tannic acid R. A
yellowish-white, flocculent precipitate is formed which
dissolves in dilute ammonia R1.
C. In a test-tube about 160 mm in length, thoroughly mix
1 g with 2 g of finely powdered manganese sulphate R.
Introduce to a depth of 2 cm into the upper part of the
tube a strip of filter paper impregnated with a freshly
prepared mixture of 1 volume of a 200 g/l solution of
diethanolamine R and 11 volumes of a 50 g/l solution
of sodium nitroprusside R, adjusted to about pH 9.8
with 1 M hydrochloric acid. Insert the tube 8 cm into a
silicone-oil bath and heat at 190-200 °C. The filter paper
becomes blue within 10 min. Carry out a blank test.
D. Dissolve 0.2 g completely, without heating, in 15 ml of a
700 g/l solution of sulphuric acid R. Pour the solution
with stirring into 100 ml of iced water R and dilute to
250 ml with iced water R. In a test-tube, mix thoroughly
while cooling in iced water 1 ml of the solution with
8 ml of sulphuric acid R, added dropwise. Heat on a
water-bath for exactly 3 min and immediately cool in iced
water. While the mixture is cold, carefully add 0.6 ml of
ninhydrin solution R2 and mix well. Allow to stand at
25 °C. A pink colour is produced immediately and does
not become violet within 100 min.
TESTS
Solution S. Disperse a quantity of the substance to be
examined equivalent to 1.0 g of the dried substance in
50 ml of carbon dioxide-free water R. After 10 min, dilute
to 100 ml with carbon dioxide-free water R and stir until
dissolution is complete.
pH (2.2.3) : 5.5 to 8.5 for solution S.
the value stated on the label.
While stirring, introduce a quantity of the substance to be
examined equivalent to 2.00 g of the dried substance into
50 g of water R. Dilute to 100.0 g with water R and stir until
dissolution is complete. Determine the viscosity using a
rotating viscometer at 25 °C and at a shear rate of 100 sí1
for substances with an expected viscosity up to 100 mPa·s,
at a shear rate of 10 sí 1 for substances with an expected
viscosity between 100 mPa·s and 20 000 mPa·s and at a shear
rate of 1 sí 1 for substances with an expected viscosity above
20 000 mPa·s. If it is impossible to obtain a shear rate of
exactly 1 sí 1, 10 sí 1 or 100 sí 1 respectively, use a rate slightly
higher and a rate slightly lower and interpolate.
EUROPEAN PHARMACOPOEIA 4.7 Hydroxyethylcellulose

Chlorides (2.4.4) : maximum 1.0 per cent. Limit :

Dilute 1 ml of solution S to 30 ml with water R. 15 ml of the — ethylene oxide : maximum 1 ppm.
solution complies with the limit test for chlorides.
Nitrates : maximum 3.0 per cent (dried substance), 2-Chloroethanol. Head-space gas chromatography (2.2.28).
if hydroxyethylcellulose has an apparent viscosity of
1000 mPa·s or less and maximum 0.2 per cent (dried Test preparation. To 50 mg of the substance to be examined
substance), if hydroxyethylcellulose has an apparent viscosity in a 10 ml vial (other size may be used depending on the
of more than 1000 mPa·s. operating conditions), add 2 µl of 2-propanol R. Seal the
flask and mix.
Determine potentiometrically (2.2.36, Method I) using as
indicator a nitrate selective electrode and a silver-silver Reference preparation (a). Dissolve 0.125 g of
chloride electrode with 0.1 M ammonium sulphate as 2-chloroethanol R and dilute to 50.0 ml with 2-propanol R.
reference electrolyte. Dilute 1.0 ml of the solution to 10.0 ml with 2-propanol R.
Prepare the solutions immediately before use. Reference preparation (b). To 50 mg of the substance to be
Buffer solution. To a mixture of 50 ml of 1 M sulphuric acid examined into an identical 10 ml vial, add 2 µl of reference
and 800 ml of water R, add 135 g of potassium dihydrogen solution (a). Seal the flask and mix.
phosphate R and dilute to 1000 ml with water R. Close the vials immediately with a butyl rubber membrane
Buffered water. Dilute 80 ml of buffer solution to 2000 ml stopper, coated with aluminium or polytetrafluoroethylene
with water R. and secured with an aluminium crimped cap.
Nitrate standard solution (500 ppm NO3). Dissolve 0.8154 g Column :
of potassium nitrate R in 500 ml of buffered water and dilute — size : l = 50 m, Ø = 0.32 mm,
to 1000.0 ml with the same solvent. — stationary phase : poly(dimethyl)siloxane R (1.2 µm).
Test solution. Dissolve 0.50 g of the substance to be Carrier gas : helium for chromatography R.
examined in buffered water and dilute to 100.0 ml with the
same solvent. Flow rate : 25-35 cm/s.
Reference solutions. If hydroxyethylcellulose has an Split ratio : 1:10.
apparent viscosity of 1000 mPa·s or less, dilute 10.0 ml, Static head-space conditions which may be used :
20.0 ml and 40.0 ml of nitrate standard solution (500 ppm — equilibration temperature : 110 °C,
NO3) to 100.0 ml with buffered water and mix.
— equilibration time : 20 min,
If hydroxyethylcellulose has an apparent viscosity of more
than 1000 mPa·s, dilute 1.0 ml, 2.0 ml and 4.0 ml of nitrate — temperature of injection system : 115 °C.
standard solution (500 ppm NO3) to 100.0 ml with buffered Temperature :
water and mix. Time Temperature
Carry out the measurements for each solution. Calculate the (min) (°C)
concentration of nitrates using the calibration curve. Column 0-6 60
Glyoxal : maximum 20 ppm. 6 - 16 60 → 110
Introduce 1.0 g into a test tube with a ground-glass
16 - 31 110 → 230
stopper and add 10.0 ml of ethanol R. Stopper the tube
and stir mechanically for 30 min. Centrifuge. To 2.0 ml 31 - 36 230
of the supernatant liquid add 5.0 ml of a 4 g/l solution Injection port 150
of methylbenzothiazolone hydrazone hydrochloride R
in an 80 per cent V/V solution of glacial acetic acid R in Detector 250
water R. Shake to homogenise. After 2 h, the solution is not
more intensely coloured than a standard prepared at the Detection : flame ionisation.
same time and in the same manner using 2.0 ml of glyoxal Injection : 2 ml.
standard solution (2 ppm C2H2O2) R instead of the 2.0 ml Retention time : 2-chloroethanol = about 7.8 min.
of supernatant liquid.
Limit :
Ethylene oxide. Head-space gas chromatography (2.4.25). — 2-chloroethanol : not more than 0.5 times the area of
Test preparation. Place 1.00 g of the substance to be the peak due to 2-chloroethanol in reference solution (b)
examined in a 5 ml vial (other sizes may be used depending (10 ppm).
on the operating conditions) and add 1 ml of water R. It
swells in water but does not dissolve. Heavy metals (2.4.8) : maximum 20 ppm.
Reference preparation (a). Place 1.00 g of the substance to 1.0 g complies with limit test C. Prepare the standard using
be examined into an identical 5 ml vial. Add 0.2 ml of cooled 2 ml of lead standard solution (10 ppm Pb) R.
ethylene oxide solution R2 and 0.8 ml of water R. It swells Loss on drying (2.2.32) : maximum 10.0 per cent, determined
in water but does not dissolve. on 1.000 g by drying in an oven at 100-105 °C for 3 h.
Reference preparation (b). To 0.1 ml of ethylene oxide Sulphated ash (2.4.14) : maximum 4.0 per cent, determined
solution R2 in a 5 ml vial add 0.1 ml of a freshly prepared on 1.0 g.
10 mg/l solution of acetaldehyde R.
Close the vials immediately with a butyl rubber membrane LABELLING
stopper, coated with aluminium or polytetrafluoroethylene The label states the apparent viscosity, in millipascal seconds
and secured with an aluminium crimped cap. for a 2 per cent m/m solution.

General Notices (1) apply to all monographs and other texts 4497
EUROPEAN PHARMACOPOEIA 4.7

L
Lauroyl macrogolglycerides.. ................................................ 4501 Liquorice ethanolic liquid extract, standardised.. ............4502
Linoleoyl macrogolglycerides................................................4502 Liquorice root.. .........................................................................4503

General Notices (1) apply to all monographs and other texts 4499
EUROPEAN PHARMACOPOEIA 4.7 Lauroyl macrogolglycerides

01/2002:1231 Hydroxyl value (2.5.3, Method A). The ranges are presented
corrected in Table 1231.-2, determined on 1.0 g.
Table 1231.-2
LAUROYL MACROGOLGLYCERIDES Ethylene oxide units Type of macrogol Hydroxyl value
per molecule
(nominal value)
Macrogolglyceridorum laurates 6 300 65 to 85
8 400 60 to 80
DEFINITION 12 600 50 to 70
Lauroyl macrogolglycerides are mixtures of monoesters, 32 1500 36 to 56
diesters and triesters of glycerol and monoesters and diesters
of macrogols with a mean relative molecular mass between Peroxide value (2.5.5). Not more than 6.0, determined on
300 and 1500. They are obtained by partial alcoholysis of 2.0 g.
saturated oils mainly containing triglycerides of lauric acid
using macrogol or by esterification of glycerol and macrogol Saponification value (2.5.6). The ranges are presented in
with saturated fatty acids or by mixing of glycerol esters and Table 1231.-3, determined on 2.0 g.
condensates of ethylene oxide with the fatty acids of these Table 1231.-3
hydrogenated oils.
Ethylene oxide units Type of macrogol Saponification value
per molecule
CHARACTERS (nominal value)
6 300 190 to 204
Pale yellow waxy solids, dispersible in hot water, freely
soluble in methylene chloride. 8 400 170 to 190
12 600 150 to 170
IDENTIFICATION 32 1500 79 to 93
A. Examine by thin-layer chromatography (2.2.27), using a
suitable silica gel as the coating substance. Alkaline impurities. Introduce 5.0 g into a test tube and
carefully add a mixture, neutralised if necessary with 0.01 M
Test solution. Dissolve 1.0 g of the substance to be hydrochloric acid or with 0.01 M sodium hydroxide,
examined in methylene chloride R and dilute to 20 ml of 0.05 ml of a 0.4 g/l solution of bromophenol blue R
with the same solvent. in alcohol R, 0.3 ml of water R and 10 ml of alcohol R.
Apply to the plate 10 µl of the test solution. Develop Shake and allow to stand. Not more than 1.0 ml of 0.01 M
over a path of 15 cm using a mixture of 30 volumes of hydrochloric acid is required to change the colour of the
hexane R and 70 volumes of ether R. Allow the plate to upper layer to yellow.
dry in air. Spray with a 0.1 g/l solution of rhodamine B R Free glycerol. Not more than 3.0 per cent. Dissolve 1.20 g
in alcohol R and examine in ultraviolet light at 365 nm. in 25.0 ml of methylene chloride R. Heat if necessary. After
The chromatogram shows a spot corresponding to cooling, add 100 ml of water R. Shake and add 25.0 ml
triglycerides with an Rf value of about 0.9 (Rst 1) and of a 6 g/l solution of periodic acid R. Shake and allow
spots corresponding to 1,3-diglycerides (Rst 0.7), to to stand for 30 min. Add 40 ml of a 75 g/l solution of
1,2-diglycerides (Rst 0.6), to monoglycerides (Rst 0.1) and potassium iodide R. Allow to stand for 1 min. Add 1 ml of
to esters of macrogol (Rst 0). starch solution R. Titrate the iodine with 0.1 M sodium
thiosulphate. Carry out a blank titration.
B. They comply with the test for hydroxyl value (see Tests).
1 ml of 0.1 M sodium thiosulphate is equivalent to 2.3 mg
C. They comply with the test for fatty acid composition (see of glycerol.
Tests).
Composition of fatty acids (2.4.22, Method A). The fatty acid
D. They comply with the test for saponification value (see fraction has the following composition :
Tests). — caprylic acid : not more than 15.0 per cent,
— capric acid : not more than 12.0 per cent,
TESTS
— lauric acid : 30.0 per cent to 50.0 per cent,
Drop point (2.2.17). Introduce into the cup the substance to — myristic acid : 5.0 per cent to 25.0 per cent,
be examined which has been melted by heating for 1 h in an
oven at 100 ± 2 °C and allow to stand for 5 h at about 5 °C. — palmitic acid : 4.0 per cent to 25.0 per cent,
The drop point is indicated in Table 1231.-1. — stearic acid : 5.0 per cent to 35.0 per cent.
Ethylene oxide and dioxan (2.4.25). Not more than 1 ppm
Table 1231.-1 of ethylene oxide and not more than 10 ppm of dioxan.
Ethylene oxide units Type of macrogol Drop point Heavy metals (2.4.8). 2.0 g complies with limit test C for
per molecule
(nominal value)
heavy metals (10 ppm). Prepare the standard using 2 ml of
lead standard solution (10 ppm Pb) R.
6 300 33 to 38
Water (2.5.12). Not more than 1.0 per cent, determined
8 400 36 to 41
on 1.0 g by the semi-micro determination of water using
12 600 38 to 43 a mixture of 30 volumes of anhydrous methanol R and
32
70 volumes of methylene chloride R as solvent.
1500 42.5 to 47.5
Total ash (2.4.16). Not more than 0.1 per cent, determined
Acid value (2.5.1). Not more than 2.0, determined on 2.0 g. on 1.0 g.

General Notices (1) apply to all monographs and other texts 4501