Edition: BP 2025 (Ph. Eur. 11.6 update)
(Ph. Eur. monograph 1757)
C16H16ClN3O3S 365.8
Action and use
Thiazide-like diuretic.
Ph Eur
DEFINITION
(2RS)-7-Chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide.
Content
97.0 per cent to 102.0 per cent (dried substance).
CHARACTERS
Appearance
White or slightly yellowish, crystalline powder.
Solubility
Very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethyl acetate, very slightly soluble in methylene chloride.
It shows polymorphism (5.9).
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison metolazone CRS.
If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in anhydrous ethanol R, evaporate to dryness and record new spectra using the residues.
TESTS
Related substances
Liquid chromatography (2.2.29).
Test solution (a) Dissolve 30.0 mg of the substance to be examined in methanol R and dilute to 10.0 mL with the same solvent.
Test solution (b) Dilute 2.0 mL of test solution (a) to 100.0 mL with methanol R.
Reference solution (a) Dissolve 3.0 mg of metolazone for system suitability CRS (containing impurities A, B, C, D and E) in 1 mL of methanol R.
Reference solution (b) Dilute 1.0 mL of test solution (a) to 100.0 mL with methanol R. Dilute 5.0 mL of this solution to 10.0 mL with methanol R.
Reference solution (c) Dissolve 30.0 mg of metolazone CRS in methanol R and dilute to 10.0 mL with the same solvent. Dilute 2.0 mL of this solution to 100.0 mL with methanol R.
Column:
– size: l = 0.25 m, Ø = 4.6 mm;
– stationary phase: octadecylsilyl silica gel for chromatography R (5 μm);
– temperature: 30 °C.
Mobile phase:
– mobile phase A: 5.44 g/L solution of potassium dihydrogen phosphate R;
– mobile phase B: methanol R;
| Time (min) | Mobile phase A (per cent V/V) | Mobile phase B (per cent V/V) |
|---|---|---|
| 0 – 5 | 70 | 30 |
| 5 – 25 | 70 → 50 | 30 → 50 |
| 25 – 35 | 50 | 50 |
| 35 – 38 | 50 → 70 | 50 → 30 |
| 38 – 48 | 70 | 30 |
Flow rate 1.5 mL/min.
Detection Spectrophotometer at 230 nm.
Injection 10 μL of test solution (a) and reference solutions (a) and (b).
Identification of impurities Use the chromatogram supplied with metolazone for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A, B, C, D and E.
System suitability Reference solution (a):
– resolution: minimum 1.6 between the peaks due to impurities E and C and minimum 1.5 between the peaks due to impurities A and B.
Limits:
– impurities A, B, C, D, E: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent);
– unspecified impurities: for each impurity, not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);
– total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent);
– disregard limit: 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).
Loss on drying (2.2.32)
Maximum 1.0 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 1.0 g.
ASSAY
Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.
Injection Test solution (b) and reference solution (c).
Calculate the percentage content of C16H16ClN3O3S from the declared content of metolazone CRS.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A, B, C, D, E.
A. (2RS)-7-chloro-2-methyl-3-(3-methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide,
B. (2RS)-7-chloro-2-methyl-3-(4-methylphenyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide,
C. (2RS)-7-chloro-2-methyl-4-oxo-3-phenyl1,2,3,4-tetrahydroquinazoline-6-sulfonamide,
D. 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6-sulfonamide,
E. 2-amino-4-chloro-N-(2-methylphenyl)-5-sulfamoylbenzamide.
Ph Eur
