EUROPEAN PHARMACOPOEIA 11.

0 Verapamil hydrochloride

Mobile phase : mix 510 volumes of acetonitrile R and

1490 volumes of a solution prepared as follows : dissolve 17 g
of ammonium dihydrogen phosphate R in 1490 mL of water R
and adjust to pH 4.4 using phosphoric acid R.
Flow rate : 1.2 mL/min.
Detection : spectrophotometer at 225 nm.
C. 1-[(1RS)-2-amino-1-(4-methoxyphenyl)ethyl]-
Injection : 20 μL.
cyclohexanol,
Run time : 10 times the retention time of venlafaxine.
Relative retention with reference to venlafaxine
(retention time = about 9 min) : impurity D = about 0.9 ;
impurity F = about 3.4.
System suitability : reference solution (b) :
– resolution : minimum 1.5 between the peaks due to
impurity D and venlafaxine. D. 1-[(1RS)-1-(4-methoxyphenyl)-2-(methylamino)ethyl]-
Limits : cyclohexanol,
– impurity F : not more than the area of the principal peak
in the chromatogram obtained with reference solution (a)
(0.1 per cent) ;
– unspecified impurities : for each impurity, not more than the
area of the principal peak in the chromatogram obtained
with reference solution (a) (0.10 per cent) ;
– total : not more than twice the area of the principal peak E. (5RS)-5-(4-methoxyphenyl)-3-methyl-1-oxa-3-
in the chromatogram obtained with reference solution (a) azaspiro[5.5]undecane,
(0.2 per cent) ;
– disregard limit : 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (a)
(0.05 per cent).
Loss on drying (2.2.32) : maximum 0.5 per cent, determined
on 1.000 g by drying in vacuo at 80 °C for 3 h.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on F. (2RS)-2-(cyclohex-1-enyl)-2-(4-methoxyphenyl)-N,N-
1.0 g. dimethylethanamine,
ASSAY
Dissolve 0.250 g in a mixture of 5.0 mL of 0.01 M hydrochloric
acid and 50 mL of ethanol (96 per cent) R. Carry out a
potentiometric titration (2.2.20), using 0.1 M sodium
hydroxide. Read the volume added between the 2 points of
inflexion. Carry out a blank titration.
1 mL of 0.1 M sodium hydroxide is equivalent to 31.39 mg G. (2RS)-2-cyclohexyl-2-(4-methoxyphenyl)-N,N-
of C17H28ClNO2. dimethylethanamine,

IMPURITIES
Specified impurities : F.
Other detectable impurities (the following substances would,
if present at a sufficient level, be detected by one or other of
the tests in the monograph. They are limited by the general
acceptance criterion for other/unspecified impurities and/or H. 1-[(1RS)-1-(4-methoxyphenyl)-2-[[2-(4-methoxyphenyl)-
by the general monograph Substances for pharmaceutical ethyl]amino]ethyl]cyclohexanol.
use (2034). It is therefore not necessary to identify these
impurities for demonstration of compliance. See also 5.10. 01/2022:0573
Control of impurities in substances for pharmaceutical use): A,
B, C, D, E, G, H.

VERAPAMIL HYDROCHLORIDE
Verapamili hydrochloridum
A. 2-(4-methoxyphenyl)-N,N-dimethylethanamine,

B. ethyl (2RS)-3-(dimethylamino)-2-(4-methoxyphenyl)- C27H39ClN2O4 Mr 491.1

propanoate, [152-11-4]

General Notices (1) apply to all monographs and other texts 4361
Verapamil hydrochloride EUROPEAN PHARMACOPOEIA 11.0

DEFINITION Reference solution (a). Dissolve 5 mg of verapamil

(2RS)-2-(3,4-Dimethoxyphenyl)-5-[[2-(3,4- hydrochloride CRS, 5 mg of verapamil impurity I CRS and
dimethoxyphenyl)ethyl](methyl)amino]-2-(prop- 5 mg of verapamil impurity M CRS in the solvent mixture and
an-2-yl)pentanenitrile hydrochloride. dilute to 20 mL with the solvent mixture. Dilute 1 mL of this
Content : 99.0 per cent to 101.0 per cent (dried substance). solution to 10 mL with the solvent mixture.
Reference solution (b). Dilute 1.0 mL of the test solution to
CHARACTERS 100.0 mL with the solvent mixture. Dilute 1.0 mL of this
Appearance : white or almost white, crystalline powder. solution to 10.0 mL with the solvent mixture.
Solubility : soluble in water, freely soluble in methanol, Column :
sparingly soluble in ethanol (96 per cent). – size : l = 0.25 m, Ø = 4.6 mm ;
IDENTIFICATION – stationary phase : end-capped polar-embedded octadecylsilyl
First identification : B, D. amorphous organosilica polymer R (5 μm).
Second identification : A, C, D. Mobile phase :
A. Ultraviolet and visible absorption spectrophotometry – mobile phase A : 6.97 g/L solution of dipotassium hydrogen
(2.2.25). phosphate R adjusted to pH 7.20 with phosphoric acid R ;
Test solution. Dissolve 20.0 mg in a 1.03 g/L solution of – mobile phase B : acetonitrile R ;
hydrochloric acid R and dilute to 100.0 mL with the same Time Mobile phase A Mobile phase B
acid. Dilute 5.0 mL of this solution to 50.0 mL with a (min) (per cent V/V) (per cent V/V)
1.03 g/L solution of hydrochloric acid R. 0 - 22 63 37
Spectral range : 210-340 nm.
22 - 27 63 → 35 37 → 65
Absorption maxima : 229 nm and 278 nm.
Shoulder : 282 nm. 27 - 45 35 65
Absorbance ratio : A278/A229 = 0.35 to 0.39.
Flow rate : 1.5 mL/min.
B. Infrared absorption spectrophotometry (2.2.24).
Detection : spectrophotometer at 278 nm.
Comparison : verapamil hydrochloride CRS.
Injection : 10 μL.
C. Thin-layer chromatography (2.2.27).
Relative retention with reference to verapamil
Test solution. Dissolve 10 mg of the substance to be (retention time = about 15 min): impurity I = about 1.3 ;
examined in methylene chloride R and dilute to 5 mL with impurity M = about 2.4.
the same solvent.
System suitability : reference solution (a) :
Reference solution (a). Dissolve 20 mg of verapamil
hydrochloride CRS in methylene chloride R and dilute to – resolution : minimum 4.5 between the peaks due to
10 mL with the same solvent. verapamil and impurity I ;
Reference solution (b). Dissolve 5 mg of papaverine – impurity M elutes from the column.
hydrochloride CRS in reference solution (a) and dilute to Limits :
5 mL with the same solution. – unspecified impurities : for each impurity, not more than the
Plate : TLC silica gel F254 plate R. area of the principal peak in the chromatogram obtained
Mobile phase : diethylamine R, cyclohexane R (15:85 V/V). with reference solution (b) (0.10 per cent) ;
Application : 5 μL. – total : not more than 3 times the area of the principal peak
Development : over 3/4 of the plate. in the chromatogram obtained with reference solution (b)
Drying : in air. (0.3 per cent);
Detection : examine in ultraviolet light at 254 nm. – disregard limit : 0.5 times the area of the principal peak in
the chromatogram obtained with reference solution (b)
System suitability : reference solution (b): (0.05 per cent).
– the chromatogram shows 2 clearly separated principal
spots. Loss on drying (2.2.32) : maximum 0.5 per cent, determined
on 1.000 g by drying in an oven at 105 °C.
Results : the principal spot in the chromatogram obtained
with the test solution is similar in position and size to Sulfated ash (2.4.14): maximum 0.1 per cent, determined on
the principal spot in the chromatogram obtained with 1.0 g.
reference solution (a).
ASSAY
D. Dissolve about 28 mg in 2 mL of methanol R. The solution
gives reaction (a) of chlorides (2.3.1) ; use methanol R Dissolve 0.400 g in 50 mL of anhydrous ethanol R and add
instead of water R to wash the precipitate. 5.0 mL of 0.01 M hydrochloric acid. Titrate with 0.1 M sodium
hydroxide, determining the end-point potentiometrically
TESTS (2.2.20). Measure the volume added between the 2 points of
inflexion.
Solution S. Dissolve 1.0 g in carbon dioxide-free water R with
gentle heating and dilute to 20.0 mL with the same solvent. 1 mL of 0.1 M sodium hydroxide is equivalent to 49.11 mg of
C27H39ClN2O4.
Appearance of solution. Solution S is clear (2.2.1) and
colourless (2.2.2, Method II). STORAGE
pH (2.2.3): 4.5 to 6.0 for solution S. Protected from light.
Optical rotation (2.2.7): − 0.10° to + 0.10°, determined on
IMPURITIES
solution S.
Other detectable impurities (the following substances would,
Related substances. Liquid chromatography (2.2.29). if present at a sufficient level, be detected by one or other of
Solvent mixture : mobile phase B, mobile phase A (37:63 V/V). the tests in the monograph. They are limited by the general
Test solution. Dissolve 25.0 mg of the substance to be acceptance criterion for other/unspecified impurities and/or
examined in the solvent mixture and dilute to 10.0 mL with by the general monograph Substances for pharmaceutical
the solvent mixture. use (2034). It is therefore not necessary to identify these

4362 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 11.0 Verapamil hydrochloride

impurities for demonstration of compliance. See also 5.10.

Control of impurities in substances for pharmaceutical use): A,
B, C, D, E, F, G, H, I, J, K, L, M, N, O, P.

J. (2RS)-2-(3,4-dimethoxyphenyl)-5-[[2-(3,4-dimethoxy-
phenyl)ethyl]amino]-2-(propan-2-yl)pentanenitrile
A. N1,N3-bis[2-(3,4-dimethoxyphenyl)ethyl]-N1,N3-dimethyl- (norverapamil),
propane-1,3-diamine,

B. 2-(3,4-dimethoxyphenyl)-N-methylethan-1-amine,
K. (2RS)-2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile,

C. 2-(3,4-dimethoxyphenyl)-N,N-dimethylethan-1-amine,

L. 1-(3,4-dimethoxyphenyl)-2-methylpropan-1-one,

D. 3-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-
methylpropan-1-amine,

E. (3,4-dimethoxyphenyl)methanol,

M. 5,5′-[[2-(3,4-dimethoxyphenyl)ethyl]azanediyl]bis[(2Ξ)-2-
(3,4-dimethoxyphenyl)-2-(propan-2-yl)pentanenitrile],

F. (2RS)-2-(3,4-dimethoxyphenyl)-5-(methylamino)-2-
(propan-2-yl)pentanenitrile,

G. 3,4-dimethoxybenzaldehyde, N. 5,5′-(methylazanediyl)bis[(2Ξ)-2-(3,4-dimethoxyphenyl)-
2-(propan-2-yl)pentanenitrile],

H. (2RS)-2-(3,4-dimethoxyphenyl)-5-[[2-(3,4-
dimethoxyphenyl)ethyl](methyl)amino]-2-
ethylpentanenitrile, O. (2RS)-2-(3,4-dimethoxyphenyl)-5-[[2-(3,4-dimethoxy-
phenyl)ethyl](methyl)amino]-2-propylpentanenitrile,

I. (2RS)-2-(3,4-dimethoxyphenyl)-4-[[2-(3,4-
dimethoxyphenyl)ethyl](methyl)amino]-2-(propan-2- P. (2Ξ,6Ξ)-2,6-bis(3,4-dimethoxyphenyl)-2,6-di(propan-2-
yl)butanenitrile, yl)heptane-1,7-dinitrile.

General Notices (1) apply to all monographs and other texts 4363