Chlorothiazide
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C7H6ClN3O4S2 295.73

2H-1,2,4-Benzothiadiazine-7-sulfonamide,6-chloro-,1,1-dioxide.
6-Chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide [58-94-6].
»Chlorothiazide contains not less than 98.0percent and not more than 102.0percent of C7H6ClN3O4S2,calculated on the dried basis.
Packaging and storage— Preserve in well-closed containers.Store at 25,excursions permitted between 15and 30.
Identification—
A: Infrared Absorption á197Mñ:previously dried at 105for 1hour.
B:Ultraviolet Absorption á197Uñ—
Solution: 10µg per mL.
Medium: sodium hydroxide solution (1in 250).
Absorptivities at 292nm,calculated on the dried basis,do not differ by more than 3.0%.
Loss on drying á731ñ— Dry it at 105for 1hour:it loses not more than 1.0%of its weight.
Residue on ignition á281ñ: not more than 0.1%.
Chloride— Dissolve 1.00g in a mixture of 10mLof water and 10mLof sodium hydroxide solution (1in 10).Cool in an ice bath,and add 20mLof water and 5mLof nitric acid.Aflocculent,white precipitate is formed.Titrate potentiometrically with 0.050Nsilver nitrate,using a silver–silver chloride electrode system:not more than 0.28mLis required (0.05%).
Selenium á291ñ: 0.003%.
Related compounds—
Mobile phase,Resolution solution,and Chromatographic system— Proceed as directed in theAssay.
Standard solution— Dissolve an accurately weighed quantity of USP Benzothiadiazine Related Compound A RSinMobile phase to obtain a solution having a known concentration of about 1.5µg per mL.
Test solution— Proceed as directed forAssay preparation in theAssay.
Procedure— Separately inject equal volumes (about 20µL)of theStandard solutionand theTest solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.The relative retention times are about 0.9for benzothiadiazine related compound Aand 1.0for chlorothiazide.Calculate the quantity,in mg,of benzothiadiazine related compound Ain the portion of Chlorothiazide taken by the formula:
0.2C(rU/rS),
in whichCis the concentration,in µg per mL,of USP Benzothiadiazine Related Compound A RSin theStandard solution;andrUandrSare the peak responses of benzothiadiazine related compound Aobtained from theTest solutionand theStandard solution,respectively:not more than 1.0%is present.
Organic volatile impurities,Method Vá467ñ: meets the requirements.
Solvent— Use dimethyl sulfoxide.
Assay—
Mobile phase— Prepare a suitable degassed mixture of 0.1Mmonobasic sodium phosphate and acetonitrile (9:1),adjust with phosphoric acid to a pHof 3.0±0.1,and filter.Make adjustments if necessary (seeSystem SuitabilityunderChromatography á621ñ).
Resolution solution— Dissolve quantities of USP Reference Standards inMobile phase to obtain solutions having known concentrations of about 0.15mg per mLof USP Chlorothiazide RSand about 1.5µg per mLof USP Benzothiadiazine Related Compound A RS.
Standard preparation— [NOTE—Avolume of acetonitrile not exceeding 10%of the total volume of solution may be used to dissolve the reference standard.]Dissolve an accurately weighed quantity of USP Chlorothiazide RSinMobile phase to obtain a solution having a known concentration of about 0.15mg per mL.
Assay preparation— Transfer about 30mg of Chlorothiazide,accurately weighed,to a 200-mLvolumetric flask,dissolve in a small volume of acetonitrile,not exceeding 10%of the total volume of the solution,dilute withMobile phaseto 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 L1.The flow rate is about 1.2mLper minute.Chromatograph replicate injections of theStandard preparation,and record the peak responses as directed forProcedure:the relative standard deviation is not more than 1.5%.Chromatograph theResolution solution:the resolution,R,between benzothiadiazine related compound Aand chlorothiazide is not less than 3.5.
Procedure— [NOTE—TheStandard preparation and theAssay preparation should be injected immediately upon preparation.]Separately inject equal volumes (about 20µL)of theStandard preparationand theAssay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major chlorothiazide peaks.The relative retention times are about 0.9for benzothiadiazine related compound Aand 1.0for chlorothiazide.Calculate the quantity,in mg,of C7H6ClN3O4S2in the portion of Chlorothiazide taken by the formula:
200C(rU/rS),
in whichCis the concentration,in mg per mL,of USP Chlorothiazide RSin theStandard preparation;andrUandrSare the peak responses of chlorothiazide obtained from theAssay preparationand theStandard preparation,respectively.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(PA5)Pharmaceutical Analysis 5
USP28–NF23Page 445
Pharmacopeial Forum:Volume No.29(5)Page 1439
Phone Number:1-301-816-8305
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