Chlorthalidone
338.77Benzenesulfonamide, 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.
Identification—
B:
Ultraviolet Absorption 
197U
—
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.
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%.
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%).
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%).
Heavy metals, Method II 231:
0.001%.
231:
0.001%.
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%.
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.
Chromatographic Column—
| Topic/Question | Contact | Expert Committee |
| Monograph | Sujatha Ramakrishna, Ph.D.
Scientist 1-301-816-8349 |
(MDCV05) Monograph Development-Cardiovascular |
| Reference Standards | Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org |
USP32–NF27 Page 1920
Pharmacopeial Forum: Volume No. 32(1) Page 68
Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.