Chlorthalidone
;)
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 98.0percent and not more than 102.0percent of C14H11ClN2O4S,calculated on the dried basis.
Packaging and storage—
Preserve in well-closed containers.
USP Reference standards á11ñ—
USP Chlorthalidone RS.USP4¢-Chloro-3¢-sulfamoyl-2-benzophenone Carboxylic Acid RS.
Identification—
A:
Infrared Absorption á197Mñ.
B:
Ultraviolet Absorption á197Uñ—
Solution:
100µg per mL.
Medium:
2Nhydrochloric acid in methanol (1in 50).
Absorptivities at 275nm,calculated on the dried basis,do not differ by more than 4.0%.
C:
Dissolve about 50mg in 3mLof sulfuric acid:an intense yellow color develops.
Loss on drying á731ñ—
Dry about 2g,accurately weighed,at 105
for 4hours:it loses not more than 0.4%of its weight.
for 4hours:it loses not more than 0.4%of its weight.
Residue on ignition á281ñ:
not more than 0.1%.
Chloride á221ñ—
Shake 1.0g with 40mLof water for 5minutes,and filter through chloride-free filter paper previously rinsed with water:the filtrate shows no more chloride than corresponds to 0.50mLof 0.020Nhydrochloric acid (0.035%).
Heavy metals,Method IIá231ñ:
0.001%.
Limit of 4¢-chloro-3¢-sulfamoyl-2-benzophenone carboxylic acid (CCA)—
Proceed as directed in the Assay,except to calculate the quantity,in mg,of CCAin the portion of Chlorthalidone taken by the formula:
(0.5)C(RU/RS),
in which Cis the concentration,in µg per mL,of USP4¢-Chloro-3¢-sulfamoyl-2-benzophenone Carboxylic Acid RSin the Standard preparation,and RUand RSare the peak response ratios of CCAand the internal standard obtained from the Assay preparationand the Standard preparation,respectively:not more than 1.0%is present.
Assay—
Mobile phase—
Prepare a suitable degassed mixture of 0.01Mdibasic ammonium phosphate and methanol (3:2),adjust dropwise with phosphoric acid to a pHof 5.5±0.1,and filter.
Internal standard solution—
Prepare a solution of 2,7-naphthalenediol in methanol having a concentration of about 1.0mg per mL.
CCAsolution—
Prepare a solution of USP4¢-Chloro-3¢-sulfamoyl-2-benzophenone Carboxylic Acid RSin methanol having a known concentration of about 5µg per mL.
Standard preparation—
Prepare a solution of USP Chlorthalidone RSin methanol having a known concentration of about 1mg per mL.Pipet 5mLof this solution into a 50-mLvolumetric flask containing 5.0mLof Internal standard solutionand 10.0mLof CCAsolution.Dilute with water to volume,and mix.
Assay preparation—
Transfer about 50mg of Chlorthalidone,accurately weighed,to a 50-mLvolumetric flask,dissolve in and dilute with methanol to volume,and mix.Pipet 5mLof this solution into a 50-mLvolumetric flask containing 5.0mLof Internal standard solutionand 10.0mLof methanol.Dilute with water to volume,and mix.
Chromatographic system
(see Chromatography á621ñ)—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 1.0mLper minute.Chromatograph five replicate injections of the Standard preparation,and record the peak responses as directed for Procedure:the relative standard deviation is not more than 2.0%,and the resolution factors between Chlorthalidone and CCA,and between chlorthalidone and the internal standard,are not less than 1.5.The tailing factors for the Chlorthalidone and CCApeaks are not more than 2.0.
Procedure—
Separately inject equal volumes (about 25µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.The relative retention times are about 0.5for CCA,0.8for Chlorthalidone and 1.0for the internal standard.Calculate the quantity,in mg,of C14H11ClN2O4Sin the portion of Chlorthalidone taken by the formula:
500C(RU/RS),
in which Cis the concentration,in mg per mL,of USP Chlorthalidone RSin the Standard preparation,and RUand RSare the peak response ratios of chlorthalidone and the internal standard obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information—
Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(PA5)Pharmaceutical Analysis 5
USP28–NF23Page 460
Phone Number:1-301-816-8305