Isoconazole nitrate EUROPEAN PHARMACOPOEIA 11.

01/2021:1017 Injection : 10 μL.

Run time : twice the retention time of isoconazole.
Identification of impurities: use the chromatogram obtained
with reference solution (a) to identify the peak due to
impurity C.
ISOCONAZOLE NITRATE Relative retention with reference to isoconazole
(retention time = about 14 min) : nitrate = about 0.04 ;
impurity C = about 1.4.
Isoconazoli nitras
System suitability : reference solution (a) :
– resolution : minimum 5.0 between the peaks due to
isoconazole and impurity C.
Calculation of percentage contents :
– for each impurity, use the concentration of isoconazole
nitrate in reference solution (b).
Limits :
– unspecified impurities : for each impurity, maximum
0.10 per cent ;
C18H15Cl4N3O4 Mr 479.1
[24168-96-5] – total : maximum 0.5 per cent ;
– reporting threshold : 0.05 per cent ; disregard the peak due
DEFINITION to the nitrate ion.
1-[(2RS)-2-(2,4-Dichlorophenyl)-2-[(2,6-dichlorophenyl)me- Loss on drying (2.2.32) : maximum 0.5 per cent, determined
thoxy]ethyl]-1H-imidazole nitrate. on 1.000 g by drying in an oven at 105 °C for 2 h.
Content : 99.0 per cent to 101.0 per cent (dried substance). Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
1.0 g.
CHARACTERS
Appearance : white or almost white powder. ASSAY
Solubility : very slightly soluble in water, soluble in methanol, Dissolve 0.350 g in 75 mL of a mixture of 1 volume of
slightly soluble in ethanol (96 per cent). anhydrous acetic acid R and 7 volumes of methyl ethyl
ketone R. Titrate with 0.1 M perchloric acid, determining the
IDENTIFICATION end-point potentiometrically (2.2.20).
A. Melting point (2.2.14) : 178 °C to 182 °C. 1 mL of 0.1 M perchloric acid is equivalent to 47.91 mg
B. Infrared absorption spectrophotometry (2.2.24). of C18H15Cl4N3O4.
Comparison : isoconazole nitrate CRS. STORAGE
Protected from light.
TESTS
Solution S. Dissolve 0.20 g in methanol R and dilute to IMPURITIES
20.0 mL with the same solvent. Other detectable impurities (the following substances would,
Appearance of solution. Solution S is clear (2.2.1) and not if present at a sufficient level, be detected by one or other of
more intensely coloured than reference solution Y7 (2.2.2, the tests in the monograph. They are limited by the general
Method II). acceptance criterion for other/unspecified impurities and/or
by the general monograph Substances for pharmaceutical use
Optical rotation (2.2.7): − 0.10° to + 0.10°, determined on
(2034). It is therefore not necessary to identify these impurities
solution S.
for demonstration of compliance. See also 5.10. Control of
Related substances. Liquid chromatography (2.2.29). impurities in substances for pharmaceutical use): A, B, C.
Test solution. Dissolve 0.100 g of the substance to be examined
in the mobile phase and dilute to 10.0 mL with the mobile
phase.
Reference solution (a). Dissolve 2.5 mg of isoconazole
nitrate CRS and 2.5 mg of miconazole nitrate CRS (impurity C)
in the mobile phase, then dilute to 100 mL with the mobile
phase.
Reference solution (b). Dilute 1.0 mL of the test solution to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution
to 10.0 mL with the mobile phase. A. (1RS)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-
Column : 1-ol,
– size : l = 0.10 m, Ø = 4.6 mm ;
– stationary phase : end-capped octadecylsilyl silica gel for
chromatography R (3 μm).
Mobile phase : dissolve 6.0 g of ammonium acetate R in a
mixture of 300 mL of acetonitrile for chromatography R,
320 mL of methanol R1 and 380 mL of water for
chromatography R.
Flow rate : 2 mL/min. B. (2RS)-2-(2,4-dichlorophenyl)-2-[(2,6-dichlorophenyl)me-
Detection : spectrophotometer at 235 nm. thoxy]ethan-1-amine,

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EUROPEAN PHARMACOPOEIA 11.0 Isoflurane

– injection port : 150 °C,

– detector : 250 °C.
Detection : flame ionisation.
Injection : 1.0 μL of each solution and 1.0 μL of anhydrous
ethanol R as a blank.
Run time : until elution of the ethanol peak in the
chromatogram obtained with the reference solution.
Relative retention with reference to isoflurane (retention
C. 1-[(2RS)-2-(2,4-dichlorophenyl)-2-[(2,4- time = about 3.8 min) : acetone = about 0.75.
dichlorophenyl)methoxy]ethyl]-1H-imidazole
(miconazole). System suitability : reference solution :
– resolution : minimum of 5 between the peaks due to acetone
and to isoflurane,
01/2008:1673 – repeatability : maximum relative standard deviation 15.0 per
corrected 9.0 cent for the peak due to isoflurane after 3 injections.
Limits :
– acetone : not more than the area of the corresponding peak
in the chromatogram obtained with the reference solution
(0.01 per cent),
ISOFLURANE – any other impurity : not more than the area of the peak
due to isoflurane in the chromatogram obtained with the
Isofluranum reference solution (0.01 per cent),
– total : not more than 3 times the area of the peak due to
isoflurane in the chromatogram obtained with the reference
solution (0.03 per cent),
– disregard limit : 0.1 times the area of the peak due to
C3H2ClF5O Mr 184.5 isoflurane in the chromatogram obtained with the reference
[26675-46-7] solution (0.001 per cent).
DEFINITION Chlorides (2.4.4) : maximum 10 ppm.
To 10 mL add 10 mL of 0.01 M sodium hydroxide and shake
(2RS)-2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane.
for 3 min. To 5 mL of the upper layer add 10 mL of water R.
CHARACTERS Fluorides : maximum 10 ppm.
Appearance : clear, colourless, mobile, heavy liquid. Determine by potentiometry (2.2.36, Method I) using a
Solubility : practically insoluble in water, miscible with ethanol. fluoride-selective indicator-electrode and a silver-silver
bp : about 48 °C. chloride reference electrode.
Test solution. To 10.0 mL in a separating funnel, add 10 mL
It is non-flammable.
of a mixture of 30.0 mL of dilute ammonia R2 and 70.0 mL
IDENTIFICATION of distilled water R. Shake for 1 min and collect the upper
layer. Repeat this extraction procedure twice collecting the
Infrared absorption spectrophotometry (2.2.24). upper layer each time. Adjust the combined upper layers to
Preparation : examine the substance in the gaseous state. pH 5.2 using dilute hydrochloric acid R. Add 5.0 mL of fluoride
Comparison : Ph. Eur. reference spectrum of isoflurane. standard solution (1 ppm F) R and dilute to 50.0 mL with
distilled water R. To 20.0 mL of the solution add 20.0 mL of
TESTS total-ionic-strength-adjustment buffer R and dilute to 50.0 mL
Acidity or alkalinity. To 20 mL add 20 mL of carbon with distilled water R.
dioxide-free water R, shake for 3 min and allow to stand. Reference solutions. To each of 5.0 mL, 4.0 mL, 3.0 mL, 2.0 mL
Collect the upper layer and add 0.2 mL of bromocresol purple and 1.0 mL of fluoride standard solution (10 ppm F) R add
solution R. Not more than 0.1 mL of 0.01 M sodium hydroxide 20.0 mL of total-ionic-strength-adjustment buffer R and dilute
or 0.6 mL of 0.01 M hydrochloric acid is required to change to 50.0 mL with distilled water R.
the colour of the indicator. Carry out the measurements on 20 mL of each solution.
Related substances. Gas chromatography (2.2.28). Calculate the concentration of fluorides using the calibration
Test solution. The substance to be examined. curve, taking into account the addition of fluoride to the test
solution.
Reference solution. To 80 mL of anhydrous ethanol R, add
1.0 mL of the substance to be examined and 1.0 mL of Non-volatile matter : maximum 200 mg/L.
acetone R, avoiding loss by evaporation. Dilute to 100.0 mL Evaporate 10.0 mL to dryness with the aid of a stream of cold
with anhydrous ethanol R. Dilute 1.0 mL of the solution to air and dry the residue at 50 °C for 2 h. The residue weighs
100.0 mL with anhydrous ethanol R. a maximum of 2.0 mg.
Column : Water (2.5.12): maximum 1.0 mg/mL, determined on
– material : fused silica, 10.0 mL.
– size : l = 30 m, Ø = 0.32 mm, STORAGE
– stationary phase : macrogol 20 000 R (film thickness
In an airtight container, protected from light.
0.25 μm).
Carrier gas : helium for chromatography R. IMPURITIES
Flow rate : 1.0 mL/min.
Split ratio : 1:25.
Temperature :
– column : 35 °C, A. 2-(chlorodifluoromethoxy)-1,1,1-trifluoroethane,

General Notices (1) apply to all monographs and other texts 3135
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