Chlorthalidone
(klor thal' i done).
Click to View Image
C14H11ClN2O4S 338.77

Benzenesulfonamide, 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)-.
2-Chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl)benzenesulfonamide [77-36-1].
» Chlorthalidone contains not less than 98.0 percent and not more than 102.0 percent of C14H11ClN2O4S, calculated on the dried basis.
Packaging and storage— Preserve in well-closed containers.
USP Reference standards 11
USP Chlorthalidone RS Click to View Structure
USP Chlorthalidone Related Compound A RS Click to View Structure
4¢-Chloro-3¢-sulfamoyl-2-benzophenone carboxylic acid.
Identification—
B: Ultraviolet Absorption 197U
Solution: 100 µg per mL.
Medium: 2 N hydrochloric acid in methanol (1 in 50).
Absorptivities at 275 nm, calculated on the dried basis, do not differ by more than 4.0%.
C: Dissolve about 50 mg in 3 mL of sulfuric acid: an intense yellow color develops.
Loss on drying 731 Dry about 2 g, accurately weighed, at 105 for 4 hours: it loses not more than 0.4% of its weight.
Residue on ignition 281: not more than 0.1%.
Chloride 221 Shake 1.0 g with 40 mL of water for 5 minutes, and filter through chloride-free filter paper previously rinsed with water: the filtrate shows no more chloride than corresponds to 0.50 mL of 0.020 N hydrochloric acid (0.035%).
Limit of chlorthalidone related compound A— Proceed as directed in the Assay, except to calculate the percentage of chlorthalidone related compound A in the portion of Chlorthalidone taken by the formula:
0.1(CR / CT)(RU / RS)
in which CR is the concentration, in µg per mL, of USP Chlorthalidone Related Compound A RS in the Standard preparation; CT is the concentration, in mg per mL, of Chlorthalidone in the Assay preparation; and RU and RS are the peak response ratios of chlorthalidone related compound A to the internal standard obtained from the Assay preparation and the Standard preparation, respectively: not more than 1.0% is present. [note—USP Chlorthalidone Related Compound A RS is 4¢-chloro-3¢-sulfamoyl-2-benzophenone carboxylic acid (CCA). ]
Assay—
Mobile phase— Prepare a suitable degassed mixture of 0.01 M dibasic ammonium phosphate and methanol (3:2), adjust dropwise with phosphoric acid to a pH of 5.5 ± 0.1, and filter.
Internal standard solution— Prepare a solution of 2,7-naphthalenediol in methanol having a concentration of about 1.0 mg per mL.
Chlorthalidone related compound A solution— Prepare a solution of USP Chlorthalidone Related Compound A RS in methanol having a known concentration of about 5 µg per mL.
Standard preparation— Prepare a solution of USP Chlorthalidone RS in methanol having a known concentration of about 1 mg per mL. Pipet 5 mL of this solution into a 50-mL volumetric flask containing 5.0 mL of Internal standard solution and 10.0 mL of Chlorthalidone related compound A solution. Dilute with water to volume, and mix. This solution contains about 0.1 mg of chlorthalidone and about 1 µg of chlorthalidone related compound A per mL.
Assay preparation— Transfer about 50 mg of Chlorthalidone, accurately weighed, to a 50-mL volumetric flask, dissolve in and dilute with methanol to volume, and mix. Pipet 5 mL of this solution into a 50-mL volumetric flask containing 5.0 mL of Internal standard solution and 10.0 mL of methanol. Dilute with water to volume, and mix.
Chromatographic system (see Chromatography 621)—The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm × 25-cm column that contains packing L7. The flow rate is about 1.0 mL per minute. Chromatograph five replicate injections of the Standard preparation, and record the peak responses as directed for Procedure: the relative retention times are about 0.5 for chlorthalidone related compound A, 0.8 for chlorthalidone, and 1.0 for the internal standard; the resolution, R, between chlorthalidone and chlorthalidone related compound A, and between chlorthalidone and the internal standard is not less than 1.5; the tailing factor for chlorthalidone and chlorthalidone related compound A is not more than 2.0; and the relative standard deviation is not more than 2.0%.
Procedure— Separately inject equal volumes (about 25 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C14H11ClN2O4S in the portion of Chlorthalidone taken by the formula:
500C(RU / RS)
in which C is the concentration, in mg per mL, of USP Chlorthalidone RS in the Standard preparation; and RU and RS are the peak response ratios of chlorthalidone to the internal standard obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Sujatha Ramakrishna, Ph.D.
Senior Scientific Liaison
1-301-816-8349
(SM22010) Monographs - Small Molecules 2
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 2649
Pharmacopeial Forum: Volume No. 32(1) Page 68