EUROPEAN PHARMACOPOEIA 11.

0 Isradipine

Internal standard solution (b). Dilute 1 mL of internal 1 mL of 0.1 M sodium hydroxide is equivalent to 33.78 mg
standard solution (a) to 50 mL with trimethylpentane R. of C18H24ClNO3.
Test solution. To 10.0 mg of the substance to be examined,
STORAGE
add 0.5 mL of N-trimethylsilylimidazole R. Heat to 65 °C
for 10 min. Allow to cool, then add 2.0 mL of the internal Protected from light.
standard solution (b) and 2.0 mL of water R. Shake. Use the
upper layer. IMPURITIES
Reference solution (a). To 10.0 mg of the substance to be Specified impurities : B.
examined, add 0.5 mL of N-trimethylsilylimidazole R. Heat Other detectable impurities (the following substances would,
to 65 °C for 10 min. Allow to cool, then add 2.0 mL of if present at a sufficient level, be detected by one or other of
the internal standard solution (a) and 2.0 mL of water R. the tests in the monograph. They are limited by the general
Shake. Dilute 1.0 mL of the upper layer to 50.0 mL with acceptance criterion for other/unspecified impurities and/or
trimethylpentane R. by the general monograph Substances for pharmaceutical
Reference solution (b). To 10.0 mg of the substance to be use (2034). It is therefore not necessary to identify these
examined, add 0.5 mL of N-trimethylsilylimidazole R. Heat impurities for demonstration of compliance. See also 5.10.
to 65 °C for 10 min. Allow to cool, then add 2.0 mL of Control of impurities in substances for pharmaceutical use) : A.
trimethylpentane R and 2.0 mL of water R. Shake. Use the
upper layer.
Column :
– material : glass ;
– size : l = 1.5 m, Ø = 4 mm ;
– stationary phase : silanised diatomaceous earth for gas A. (1RS,2SR)-1-(4-hydroxyphenyl)-2-[[(1RS)-1-methyl-2-
chromatography R (125-135 μm) impregnated with 3 per phenoxyethyl]amino]propan-1-ol,
cent m/m of methylpolysiloxane R.
Carrier gas : nitrogen for chromatography R.
Flow rate : 30 mL/min.
Temperature :
Time Temperature
(min) (°C) B. 1-(4-hydroxyphenyl)-2-[(1-methyl-2-
Column 0 - 25 195
phenoxyethyl)amino]propan-1-one.

25 - 29 195 → 215

29 - 39 215
01/2023:2110
Injection port 225

Detector 225

Detection : flame ionisation.

Injection : 1 μL. ISRADIPINE
Elution order : isoxsuprine, hexacosane.
System suitability : Isradipinum
– resolution : minimum 5.0 between the peaks due to
isoxsurpine and hexacosane in the chromatogram obtained
with reference solution (a);
– in the chromatogram obtained with reference solution (b),
there is no peak with the same retention time as the internal
standard.
Limit :
– total : calculate the ratio (R) of the area of the peak due
to the trimethylsilyl derivative of isoxsuprine to the
C19H21N3O5 Mr 371.4
area of the peak due to the internal standard from the
[75695-93-1]
chromatogram obtained with reference solution (a); from
the chromatogram obtained with the test solution, calculate DEFINITION
the ratio of the sum of the areas of any peaks, apart from the
3-Methyl 5-(propan-2-yl) (4RS)-4-(2,1,3-benzoxadiazol-4-yl)-
principal peak and the peak due to the internal standard,
to the area of the peak due to the internal standard : this 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
ratio is not greater than R (2.0 per cent). Content : 97.0 per cent to 102.0 per cent (dried substance).
Loss on drying (2.2.32) : maximum 0.5 per cent, determined CHARACTERS
on 1.000 g by drying in an oven at 105 °C.
Appearance : yellow, crystalline powder.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on Solubility : practically insoluble in water, freely soluble in
1.0 g. acetone, soluble in methanol.
ASSAY mp : about 168 °C.
Dissolve 0.250 g in 80 mL of ethanol (96 per cent) R and add IDENTIFICATION
1.0 mL of 0.1 M hydrochloric acid. Carry out a potentiometric
titration (2.2.20), using 0.1 M sodium hydroxide. Read Infrared absorption spectrophotometry (2.2.24).
the volume added between the 2 points of inflexion. Comparison : isradipine CRS.

General Notices (1) apply to all monographs and other texts 3151
www.webofpharma.com
Isradipine EUROPEAN PHARMACOPOEIA 11.0

TESTS ASSAY
Related substances. Liquid chromatography (2.2.29). Liquid chromatography (2.2.29) as described in the test for
Test solution (a). Dissolve 50 mg of the substance to be related substances with the following modifications.
examined in 1 mL of methanol R, using an ultrasonic bath if Mobile phase : acetonitrile R, tetrahydrofuran R, water for
necessary, and dilute to 25.0 mL with the mobile phase. chromatography R (125:270:625 V/V/V).
Test solution (b). Dissolve 50.0 mg of the substance to be Detection : spectrophotometer at 326 nm.
examined in 2 mL of methanol R and dilute to 250.0 mL with Injection : test solution (b) and reference solution (d).
the mobile phase.
Run time : twice the retention time of isradipine.
Reference solution (a). Dilute 1.0 mL of test solution (a) to
100.0 mL with the mobile phase. Dilute 1.0 mL of this solution Calculate the percentage content of isradipine taking into
to 10.0 mL with the mobile phase. account the assigned content of isradipine CRS.
Reference solution (b). Dissolve 2 mg of the substance to STORAGE
be examined and 2 mg of isradipine impurity D CRS in the
mobile phase and dilute to 10 mL with the mobile phase. Protected from light.
Dilute 1 mL of this solution to 10 mL with the mobile phase.
IMPURITIES
Reference solution (c). Dissolve 10 mg of isradipine for peak
identification CRS (containing impurities A and B) in 2 mL of Specified impurities : A, B, D.
methanol R, using an ultrasonic bath if necessary, and dilute Other detectable impurities (the following substances would,
to 5 mL with the mobile phase. if present at a sufficient level, be detected by one or other of
Reference solution (d). Dissolve 50.0 mg of isradipine CRS in the tests in the monograph. They are limited by the general
2 mL of methanol R and dilute to 250.0 mL with the mobile acceptance criterion for other/unspecified impurities and/or
phase. by the general monograph Substances for pharmaceutical use
(2034). It is therefore not necessary to identify these impurities
Column : for demonstration of compliance. See also 5.10. Control of
– size : l = 0.10 m, Ø = 4.6 mm ; impurities in substances for pharmaceutical use) : C, E.
– stationary phase : end-capped octadecylsilyl silica gel for
chromatography R (5 μm).
Mobile phase : acetonitrile for chromatography R,
tetrahydrofuran R, water for chromatography R
(125:270:625 V/V/V).
Flow rate : 1.2 mL/min.
Detection : spectrophotometer at 230 nm.
Injection : 20 μL of test solution (a) and reference solutions (a),
(b) and (c). A. 5-ethyl 3-methyl (4RS)-4-(2,1,3-benzoxadiazol-4-yl)-2,6-
Run time : 5 times the retention time of isradipine. dimethyl-1,4-dihydropyridine-3,5-dicarboxylate,
Identification of impurities : use the chromatogram obtained
with reference solution (b) to identify the peak due to
impurity D ; use the chromatogram supplied with isradipine
for peak identification CRS and the chromatogram obtained
with reference solution (c) to identify the peaks due to
impurities A and B.
Relative retention with reference to isradipine
(retention time = about 7 min) : impurity A = about 0.8 ;
impurity D = about 0.9 ; impurity B = about 1.8.
B. di(propan-2-yl) 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-
System suitability : reference solution (b) :
1,4-dihydropyridine-3,5-dicarboxylate,
– resolution : minimum 2.0 between the peaks due to
isradipine and impurity D.
Calculation of percentage contents :
– correction factor : multiply the peak area of impurity D by
1.4 ;
– for each impurity, use the concentration of isradipine in
reference solution (a).
Limits :
– impurity B : maximum 0.8 per cent ; C. dimethyl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-
– impurity A : maximum 0.2 per cent ; dihydropyridine-3,5-dicarboxylate,
– impurity D : maximum 0.10 per cent ;
– unspecified impurities : for each impurity, maximum
0.10 per cent ;
– total : maximum 1.0 per cent ;
– reporting threshold : 0.05 per cent.
Loss on drying (2.2.32) : maximum 0.2 per cent, determined
on 1.000 g by drying in an oven at 105 °C for 4 h.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on D. 3-methyl 5-(propan-2-yl) 4-(2,1,3-benzoxadiazol-4-yl)-2,6-
1.0 g. dimethylpyridine-3,5-dicarboxylate,

3152 See the information section on general monographs (cover pages)

www.webofpharma.com
EUROPEAN PHARMACOPOEIA 11.0 Itraconazole

IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison : itraconazole CRS.

TESTS
Solution S. Dissolve 2.0 g in methylene chloride R and dilute
to 20.0 mL with the same solvent.
Appearance of solution. Solution S is clear (2.2.1) and not
E. mixture of 3-methyl 5-(propan-2-yl) (4RS)-4-(2,1,3- more intensely coloured than reference solution R6 or B6
benzoxadiazol-4-yl)-2-[(1EZ)-2-(2,1,3-benzoxadiazol- (2.2.2, Method II).
4-yl)ethen-1-yl]-6-methyl-1,4-dihydropyridine-
3,5-dicarboxylate and 5-methyl 3-(propan-2-yl) Related substances. Liquid chromatography (2.2.29). Prepare
(4RS)-4-(2,1,3-benzoxadiazol-4-yl)-2-[(1EZ)-2- the solutions immediately before use.
(2,1,3-benzoxadiazol-4-yl)ethen-1-yl]-6-methyl-1,4- Test solution. Dissolve 0.100 g of the substance to be examined
dihydropyridine-3,5-dicarboxylate. in methanolic hydrochloric acid R and dilute to 10.0 mL with
the same solvent.
Reference solution (a). Dilute 1.0 mL of the test solution to
100.0 mL with methanolic hydrochloric acid R. Dilute 1.0 mL
of this solution to 10.0 mL with methanolic hydrochloric
acid R.
01/2011:1335
Reference solution (b). Dissolve 10 mg of itraconazole for
system suitability CRS (containing impurities B, C, D, E, F
and G) in 1.0 mL of methanolic hydrochloric acid R.
Column :
– size : l = 0.10 m, Ø = 4.6 mm ;
ITRACONAZOLE – stationary phase : base-deactivated end-capped octadecylsilyl
silica gel for chromatography R (3 μm or 3.5 μm) ;
Itraconazolum – temperature : 30 °C.
Mobile phase :
– mobile phase A : 27.2 g/L solution of tetrabutylammonium
hydrogen sulfate R1;
– mobile phase B : acetonitrile R1 ;
Time Mobile phase A Mobile phase B
(min) (per cent V/V) (per cent V/V)
0-2 80 20
2 - 22 80 → 50 20 → 50

22 - 27 50 50

Flow rate : 1.5 mL/min.

Detection : spectrophotometer at 225 nm.
Injection : 10 μL.
Identification of impurities : use the chromatogram supplied
with itraconazole for system suitability CRS and the
chromatogram obtained with reference solution (b) to identify
the peaks due to impurities B, C, D, E, F and G.
C35H38Cl2N8O4 Mr 706
[84625-61-6] Relative retention with reference to itraconazole
(retention time = about 14 min) : impurity B = about 0.7 ;
impurities C and D = about 0.8 ; impurity E = about 0.9 ;
DEFINITION impurity F = about 1.05 ; impurity G = about 1.3.
4-[4-[4-[4-[[cis-2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol- System suitability : reference solution (b) :
1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1- – peak-to-valley ratio : minimum 1.5, where Hp = height above
yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4- the baseline of the peak due to impurity F and Hv = height
triazol-3-one. above the baseline of the lowest point of the curve
Content : 99.0 per cent to 101.0 per cent (dried substance). separating this peak from the peak due to itraconazole.
Limits :
CHARACTERS – impurities B, G : for each impurity, not more than 3 times
the area of the principal peak in the chromatogram
Appearance : white or almost white powder. obtained with reference solution (a) (0.3 per cent) ;
Solubility : practically insoluble in water, freely soluble in – impurity E : not more than twice the area of the principal
methylene chloride, very slightly soluble in ethanol (96 per peak in the chromatogram obtained with reference
cent). solution (a) (0.2 per cent);

General Notices (1) apply to all monographs and other texts 3153
www.webofpharma.com