Amlodipine Besilate

(Ph Eur monograph 1491)

C₂₀H₂₅ClN₂O₅,C₆H₆O₃S    567.1    111470-99-6

Calcium channel blocker.

Ph Eur

3-Ethyl 5-methyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate.

97.0 per cent to 102.0 per cent (anhydrous substance).

White or almost white powder.

Slightly soluble in water, freely soluble in methanol, sparingly soluble in anhydrous ethanol, slightly soluble in 2-propanol.

Infrared absorption spectrophotometry (2.2.24).

Comparison  amlodipine besilate CRS.

-  0.10°  to  +  0.10°.

Dissolve 0.250 g in methanol R and dilute to 25.0 ml with the same solvent.

Liquid chromatography (2.2.29). Carry out the test protected from light.

Test solution (a)  Dissolve 50.0 mg of the substance to be examined in methanol R and dilute to 50.0 ml with the same solvent.

Test solution (b)  Dilute 5.0 ml of test solution (a) to 100.0 ml with methanol R.

Reference solution (a)  Dilute 1.0 ml of test solution (a) to 10.0 ml with methanol R. Dilute 1.0 ml of this solution to 100.0 ml with methanol R.

Reference solution (b)  Dissolve 5 mg of amlodipine impurity B CRS and 5 mg of amlodipine impurity G CRS in methanol R and dilute to 50.0 ml with the same solvent. Dilute 1.0 ml of this solution to 10.0 ml with methanol R.

Reference solution (c)  Dissolve 5 mg of amlodipine for peak identification CRS (containing impurities D, E and F) in 10 ml of methanol R.

Reference solution (d)  Dissolve 5.0 mg of amlodipine impurity A CRS in methanol R and dilute to 5.0 ml with the same solvent. Dilute 1.0 ml of the solution to 100.0 ml with methanol R. Dilute 1.0 ml of this solution to 10.0 ml with methanol R.

Reference solution (e)  Dissolve 50.0 mg of amlodipine besilate CRS in methanol R and dilute to 50.0 ml with the same solvent. Dilute 5.0 ml of this solution to 100.0 ml with methanol R.

• — size:  l  =  0.25  m, Ø  =  4.0  mm;

• — stationary phase: octadecylsilyl silica gel for chromatography R (5 µm);

• — temperature: 30  °C.

Mobile phase  2.3 g/l solution of ammonium acetate R, methanol R (30:70 V/V).

Flow rate  1.5 ml/min.

Detection  Spectrophotometer at 237 nm.

Injection  20 µl of test solution (a) and reference solutions (a), (b), (c) and (d).

Run time  Twice the retention time of amlodipine.

Identification of impurities  Use the chromatogram supplied with amlodipine for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities D, E and F; use the chromatogram obtained with reference solution (d) to identify the peak due to impurity A.

Relative retention  With reference to amlodipine (retention  time  =  about  20  min): impurity  G  =  about  0.15; impurity  B  =  about  0.2; impurity  A  =  about  0.3; impurity  D  =  about  0.5; impurity  F  =  about  0.8; impurity  E  =  about  1.3.

System suitability  Reference solution (b):

• — resolution: minimum 2.0 between the peaks due to impurities B and G.

• — correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity  D  =  1.7; impurity  F  =  0.7;

• — impurity D: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent);

• — impurity A: not more than 1.5 times the area of the corresponding peak in the chromatogram obtained with reference solution (d) (0.15 per cent);

• — impurities E, F: for each impurity, not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 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 8 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.8 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). Disregard any peak due to benzene sulphonate (relative  retention  =  about  0.14).

Maximum 0.5 per cent, determined on 1.000 g.

Maximum 0.2 per cent, determined on 1.0 g.

Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.

Injection  Test solution (b), reference solution (e).

Calculate the percentage content of C₂₆H₃₁ClN₂0₈S from the declared content of amlodipine besilate CRS.

In an airtight container, protected from light.

Specified impurities  A, D, E, 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 by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): B, G, H.

A.  3-ethyl 5-methyl (4RS)-4-(2-chlorophenyl)-2-[[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]methyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate,

B.  R  =  NHCH₃: 3-ethyl 5-methyl (4RS)-4-(2-chlorophenyl)6-methyl-2-[[2-[[2-(methylcarbamoyl)benzoyl]amino]ethoxy]methyl]-1,4-dihydropyridine-3,5-dicarboxylate,

H.  R  =  OH: 2-[[2-[[(4RS)-4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-methoxycarbonyl)-6-methyl-1,4-dihydropyridin-2-yl]methoxy]ethyl]carbamoyl]benzoic acid,

D.  3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate,

E.  R  =  C₂H₅: diethyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate,

F.  R  =  CH₃: dimethyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate,

G.  dimethyl 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

Ph Eur