Fosfomycin trometamol EUROPEAN PHARMACOPOEIA 5.

solution of sodium hydrogen carbonate R. Add 10 ml of a IDENTIFICATION

freshly prepared 400 g/l solution of potassium iodide R, First identification : A.
close and allow to stand for 2 min. Titrate with 0.1 M sodium Second identification : B, C.
arsenite until the yellow colour almost disappears. Add
2 ml of starch solution R and titrate slowly until the colour A. Examine by infrared absorption spectrophotometry
is completely discharged. Carry out a blank test under the (2.2.24), comparing with the spectrum obtained with
same conditions. fosfomycin trometamol CRS.
Calculate the percentage content of C3H5Na2O4P from the B. Examine by thin-layer chromatography (2.2.27), using
expression : cellulose for chromatography R as the coating substance.
Test solution. Dissolve 50 mg of the substance to be
examined in water R and dilute to 10 ml with the same
solvent.
Reference solution. Dissolve 50 mg of fosfomycin
m = quantity of the substance to be examined, in trometamol CRS in water R and dilute to 10 ml with the
milligrams, same solvent.
n1 = volume of 0.1 M sodium arsenite used in the Apply to the plate 10 l of each solution. Develop
blank titration, over a path of 15 cm using a mixture of 10 volumes of
n2 concentrated ammonia R, 20 volumes of water R and
= volume of 0.1 M sodium arsenite used in the 70 volumes of 2-propanol R. Dry the plate in a current of
titration of the test solution, warm air and expose it to iodine vapour until the spots
c = molarity of the sodium arsenite solution, appear. The principal spot in the chromatogram obtained
G = percentage content of disodium with the test solution is similar in position, colour and
1,2-(dihydroxypropyl)phosphonate, size to the principal spot in the chromatogram obtained
with the reference solution.
H = percentage content of water. C. To about 15 mg of the substance to be examined,
add 2 ml of water R, 1 ml of perchloric acid R
STORAGE and 2 ml of 0.1 M sodium periodate. Heat on a
Store in an airtight container, protected from light. If the water-bath for 10 min and add, without cooling, 1 ml
substance is sterile, store in a sterile, airtight, tamper-proof of ammonium molybdate solution R5 and 1 ml of
container. aminohydroxynaphthalenesulphonic acid solution R.
Allow to stand for 30 min. A blue colour develops.
LABELLING
The label states, where applicable, that the substance is free TESTS
from bacterial endotoxins. Solution S. Dissolve 1.00 g in carbon dioxide-free water R
IMPURITIES and dilute to 20.0 ml with the same solvent.
pH (2.2.3). The pH of solution S is 3.5 to 5.5.
Specific optical rotation (2.2.7). Measured at 365 nm
using a mercury lamp, the specific optical rotation is 13.5
to 12.5, determined on solution S and calculated with
reference to the anhydrous substance.
A. disodium (1,2-dihydroxypropyl)phosphonate. Related substances. Examine by liquid chromatography
(2.2.29) as prescribed under Assay.
Inject 5 l of the test solution, 5 l of reference solution (b)
01/2005:1425 and 5 l of the blank solution. Continue the chromatography
for twice the retention time of the peak due to fosfomycin.
FOSFOMYCIN TROMETAMOL In the chromatogram obtained with the test solution :
the area of any peak corresponding to impurity A is not
Fosfomycinum trometamolum greater than the area of the corresponding peak in the
chromatogram obtained with reference solution (b) (0.5 per
cent, calculated as trometamol salts) ; the area of any peak,
apart from the principal peak, two peaks corresponding
to trometamol and any peak corresponding to impurity A,
is not greater than the area of the principal peak in the
chromatogram obtained with reference solution (b) (0.5 per
C7H18NO7P Mr 259.2 cent, calculated as trometamol salts). The sum of the areas
of all the peaks, apart from the principal peak and the two
DEFINITION peaks corresponding to trometamol, is not greater than
Fosfomycin trometamol contains not less than 98.0 per twice the area of the principal peak in the chromatogram
cent and not more than the equivalent of 102.0 per cent obtained with reference solution (b) (1 per cent, calculated
of 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium as trometamol salts). Disregard any peak due to the blank
(2R,3S)-(3-methyloxiran-2-yl)phosphonate, calculated with and any peak with an area less than 0.1 times the area of the
reference to the anhydrous substance. principal peak in the chromatogram obtained with reference
solution (b).
CHARACTERS Phosphates. Dissolve 0.1 g in 3 ml of dilute nitric acid R
A white or almost white powder, hygroscopic, very soluble in and dilute to 10 ml with water R. To 5 ml of this test solution
water, slightly soluble in alcohol and in methanol, practically add 5 ml of water R and 5 ml of molybdovanadic reagent R.
insoluble in acetone. Shake vigorously. After 5 min, any colour in the test solution

1638 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 5.0 Framycetin sulphate

is not more intense that that in a standard prepared at the

same time in the same manner, using 5 ml of phosphate
standard solution (5 ppm PO4) R (500 ppm).
Heavy metals (2.4.8). Dissolve 2.0 g in water R and dilute to
20 ml with the same solvent. 12 ml of the solution complies
with limit test A for heavy metals (10 ppm). Prepare the
standard using lead standard solution (1 ppm Pb) R. B. [2-[2-amino-3-hydroxy-2-(hydroxymethyl)propoxy]-1-
hydroxypropyl]phosphonic acid,
Water (2.5.12). Not more than 0.5 per cent, determined on
0.500 g by the semi-micro determination of water.

ASSAY
Examine the substance by liquid chromatography (2.2.29).
Prepare the solutions immediately before use.
Test solution. Dissolve 0.60 g of the substance to be
C. 2-amino-3-hydroxy-2-(hydroxymethyl)propyl
examined in the mobile phase and dilute to 5.0 ml with the
dihydrogenphosphate (trometamol phosphoric ester),
mobile phase.
Reference solution (a). Dissolve 0.60 g of fosfomycin
trometamol CRS in the mobile phase and dilute to 5.0 ml
with the mobile phase.
Reference solution (b). Dissolve 8.7 mg of fosfomycin
trometamol impurity A CRS (disodium salt) in the mobile
phase and dilute to 20.0 ml with the mobile phase.
D. [2-[[[2-[2-amino-3-hydroxy-2-(hydroxymethyl)propoxy]-
Reference solution (c). Dissolve 5 mg of fosfomycin 1-hydroxypropyl]hydroxyphosphoryl]oxy]-1-
trometamol impurity A CRS (disodium salt) and 10 mg of hydroxypropyl]phosphonic acid (trometamoyloxy
fosfomycin trometamol CRS in the mobile phase and dilute fosfomycin dimer).
to 5 ml with the mobile phase.
Blank solution. A 0.3 g/l solution of anhydrous disodium
hydrogen phosphate R in the mobile phase.
01/2005:0180
The chromatographic procedure may be carried out using : corrected
a stainless steel column 0.25 m long and 4.6 mm in
internal diameter packed with aminopropylsilyl silica gel FRAMYCETIN SULPHATE
for chromatography R (5 m),
as mobile phase at a flow rate of 1 ml/min a 10.89 g/l
solution of potassium dihydrogen phosphate R,
Framycetini sulfas
as detector a differential refractometer maintaining the
temperature at 35 C.
When the chromatograms are recorded in the prescribed
conditions, the relative retention times (to fosfomycin) are
about 0.3 for the two peaks corresponding to trometamol
and 0.8 for impurity A.
Inject 5 l of reference solution (c). The test is not valid
unless the resolution between the peaks corresponding to
fosfomycin and impurity A is at least 1.5. Inject reference
solution (a) six times. The test is not valid unless the relative C H N O ,xH SO Mr 615 (base)
standard deviation of the peak area for fosfomycin is at 23 46 6 13 2 4

most 1.0 per cent. Inject alternately the test solution and DEFINITION
reference solution (a).
Sulphate of 2-deoxy-4-O-(2,6-diamino-2,6-dideoxy--D-
Calculate the percentage content of fosfomycin trometamol. glucopyranosyl)-5-O-[3-O-(2,6-diamino-2,6-dideoxy--L-
idopyranosyl)--D-ribofuranosyl]-D-streptamine (neomycin B),
STORAGE a substance produced by the growth of selected strains of
Store in an airtight container. Streptomyces fradiae or Streptomyces decaris or obtained
by any other means.
IMPURITIES Content : minimum of 630 IU/mg (dried substance).
CHARACTERS
Appearance : white or yellowish-white powder, hygroscopic.
Solubility : freely soluble in water, very slightly soluble in
alcohol, practically insoluble in acetone.
IDENTIFICATION
A. 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium A. Examine the chromatograms obtained in the test for
(1,2-dihydroxypropyl)phosphonate, related substances.

General Notices (1) apply to all monographs and other texts 1639