Clopamide

(Ph. Eur. monograph 1747)

C₁₄H₂₀ClN₃O₃S    345.8    636-54-4

Thiazide-like diuretic.

Ph Eur

4-Chloro-N-[(2RS,6SR)-2,6-dimethylpiperidin-1-yl]-3-sulfamoylbenzamide.

99.0 per cent to 101.0 per cent (dried substance).

The production method is evaluated to determine the potential for formation of an N-nitroso compound (cis-2,6-dimethyl-1-nitrosopiperidine). Where necessary, the production method is validated to demonstrate that the N-nitroso compound is absent in the final product.

White or almost white, hygroscopic, crystalline powder.

Slightly soluble in water and in anhydrous ethanol, sparingly soluble in methanol.

It shows polymorphism (5.9).

Infrared absorption spectrophotometry (2.2.24).

Comparison   clopamide CRS.

If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in the minimum volume of methanol R, evaporate to dryness on a water-bath and record new spectra using the residues.

Liquid chromatography (2.2.29).

Test solution  Dissolve 100 mg of the substance to be examined in methanol R and dilute to 10.0 mL with the same solvent.

Reference solution (a)  Dissolve 10 mg of clopamide for system suitability CRS (containing impurities B, C and H) in 1.0 mL of methanol R.

Reference solution (b)  Dilute 2.0 mL of the test solution to 100.0 mL with methanol R. Dilute 2.0 mL of this solution to 40.0 mL with methanol R.

• — size: l = 0.15 m, Ø = 4.6 mm;

• — stationary phase: end-capped octylsilyl silica gel for chromatography R (5 µm).

• — mobile phase A: dissolve 1.0 g of ammonium acetate R in 950 mL of water R, adjust to pH 2.0 with phosphoric acid R and dilute to 1000 mL with water R;

• — mobile phase B: acetonitrile R;

• — mobile phase C: water R, tetrahydrofuran for chromatography R (20:80 V/V); this mobile phase allows adequate rinsing of the system;

Flow rate  0.4 mL/min.

Detection  Spectrophotometer at 235 nm.

Injection  10 µL.

Identification of impurities  Use the chromatogram supplied with clopamide for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities B, C and H.

Relative retention  With reference to clopamide (retention time = about 33 min): impurity C = about 0.8; impurity H = about 1.2; impurity B = about 1.4.

System suitability  Reference solution (a):

• — resolution: minimum 3 between the peaks due to impurity C and clopamide.

• — correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity B = 0.5; impurity H = 0.4;

• — impurities B, C, H: for each impurity, not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent);

• — unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);

• — total: not more than 10 times the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent);

• — disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).

Maximum 20 ppm.

Dissolve 0.25 g in a mixture of 20 volumes of acetone R and 85 volumes of methanol R and dilute to 20 mL with the same mixture of solvents. 20 mL of the solution complies with modified test B. Prepare the reference solution by diluting 0.5 mL of lead standard solution (10 ppm Pb) R to 20 mL with a mixture of 20 volumes of acetone R and 85 volumes of methanol R. Prepare the blank solution by using 20 mL of a mixture of 20 volumes of acetone R and 85 volumes of methanol R.

Filter the solutions through a membrane filter (nominal pore size 0.45 µm) to evaluate the result.

Maximum 2.5 per cent, determined on 1.000 g by drying in an oven at 105 °C.

Maximum 0.1 per cent, determined on 1.0 g.

Dissolve 0.280 g in 70 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).

1 mL of 0.1 M perchloric acid is equivalent to 34.58 mg of C₁₄H₂₀ClN₃O₃S.

In an airtight container, protected from light.

Specified impurities   B, C, H.

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): A, G.

A. R = CH₃: 4-chloro-N-[(2RS,6RS)-2,6-dimethylpiperidin-1-yl]-3-sulfamoylbenzamide (trans-clopamide),

G. R = H: 4-chloro-N-[(2RS)-2-methylpiperidin-1-yl]-3-sulfamoylbenzamide,

B. R = H: 4-chlorobenzoic acid,

C. R = SO₂-NH₂: 4-chloro-3-sulfamoylbenzoic acid,

H. 4-chloro-3-[(E)-[(dimethylamino)methylene]sulfamoyl]-N-[(2RS,6SR)-2,6-dimethylpiperidin-1-yl]benzamide.

Ph Eur