USP 30

Ofcial Monographs / Hydrochlorothiazide

Hydrochlorothiazide

ProcedureInject a volume (about 10 mL) of the Test solution into the chromatograph, record the chromatogram, and measure the peak responses. Calculate the percentage of each impurity in the portion of Hydrochlorothiazide taken by the formula: 100(ric / rsc) in which ric is the ratio of the peak area for each impurity to its response factor; and rsc is the sum of ratios of all the peak areas to their respective response factors, the response factors being 0.54, 0.63, and 1.0 for benzothiadiazine related compound A, chlorothiazide, and all other peaks, respectively: not more than 1.0% of benzothiadiazine related compound A is found; not more than 0.5% of any other impurity is found; and not more than 0.9% of total other impurities excluding benzothiadiazine related compound A is found. Organic volatile impurities, Method V h467i: meets the requirements. SolventUse dimethyl sulfoxide. (Ofcial until July 1, 2007) Assay Sodium phosphate solutionTransfer 2.76 g of monobasic sodium phosphate, accurately weighed, into a 1000-mL volumetric ask, and add about 990 mL of water. Adjust with phosphoric acid to a pH of 2.7 + 0.1, and dilute with water to volume. Make adjustments if necessary (see System Suitability under Chromatography h621i). DiluentPrepare a mixture of Sodium phosphate solution and acetonitrile (7 : 3). Solution APrepare and degas a mixture of acetonitrile and methanol (3 : 1). Solution BPrepare and degas a solution of anhydrous formic acid in water (5 in 1000). Mobile phaseUse variable mixtures of Solution A and Solution B as directed for Chromatographic system. Make adjustments if necessary (see System Suitability under Chromatography h621i). System suitability solutionDissolve suitable quantities of USP Hydrochlorothiazide RS, USP Chlorothiazide RS, and USP Benzothiadiazine Related Compound A RS in Diluent, sonicate if necessary, and dilute with Diluent to obtain a solution containing about 0.32 mg per mL, 0.0032 mg per mL, and 0.0032 mg per mL, respectively. Pass a portion through a lter having a 0.45-mm or ner porosity. Standard preparationDissolve an accurately weighed quantity of USP Hydrochlorothiazide RS in Diluent, sonicate if necessary, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.32 mg per mL. Pass a portion through a lter having a 0.45-mm or ner porosity before injection. Assay preparationTransfer about 32 mg of Hydrochlorothiazide, accurately weighed, to a 100-mL volumetric ask. Add about 70 mL of Diluent, sonicate for 10 minutes if necessary to dissolve, and allow to cool to ambient temperature. Dilute with Diluent to volume, mix, and pass a portion through a lter having a 0.45-mm or ner porosity before injection. Chromatographic system (see Chromatography h621i)The liquid chromatograph is equipped with a 275-nm detector and 4.6mm 6 5-cm column that contains 3.5-mm packing L1. The ow rate is about 1.0 mL per minute. The column temperature is maintained at 358. The chromatograph is programmed as follows. Time (minutes) 0 05 514 1418 1820 Solution A (%) 3 3 3?36 36?3 3 Solution B (%) 97 97 97?64 64?97 97 Elution equilibration isocratic linear gradient linear gradient re-equilibration

C7H8ClN3O4S2 297.74 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro, 1,1-dioxide. 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1dioxide [58-93-5].

Hydrochlorothiazide contains not less than 98.0

percent and not more than 102.0 percent of C7H8ClN3O4S2, calculated on the dried basis.

Packaging and storagePreserve in well-closed containers. USP Reference standards h11iUSP Benzothiadiazine Related Compound A RS. USP Chlorothiazide RS. USP Hydrochlorothiazide RS. Identication A: Infrared Absorption h197Ki, the potassium bromide-hydrochlorothiazide mixture previously being heated at 1058 for 2 hours. B: Ultraviolet Absorption h197Ui Solution: 10 mg per mL. Medium: methanol. Loss on drying h731iDry it at 1058 for 1 hour: it loses not more than 0.5% of its weight. Residue on ignition h281i: not more than 0.1%. Chloride h221iShake 0.50 g with 40 mL of water for 5 minutes, and lter: the ltrate shows no more chloride than corresponds to 0.25 mL of 0.020 N hydrochloric acid (0.035%). Selenium h291i: 0.003%, a 200-mg test specimen being used. Heavy metals, Method II h231i: 0.001%. Related compounds Diluent, Solution A, Solution B, Mobile phase, and System suitability solutionProceed as directed in the Assay. Quantitation limit solutionDissolve an accurately weighed quantity of USP Hydrochlorothiazide RS in Diluent, sonicate if necessary, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.16 mg per mL. Test solutionProceed as directed for the Assay preparation in the Assay. Chromatographic system (see Chromatography h621i)Prepare as directed in the Assay. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between benzothiadiazine related compound A and chlorothiazide is not less than 2.0 and the resolution, R, between chlorothiazide and hydrochlorothiazide is not less than 1.5; the tailing factor for the benzothiadiazine related compound A, chlorothiazide, and hydrochlorothiazide peaks is not more than 1.5; and the relative standard deviation for replicate injections determined from benzothiadiazine related compound A and chlorothiazide is not more than 5.0%. Chromatograph three replicate injections of the Quantitation limit solution, and record the peak responses as directed for Procedure: the relative standard deviation is not more than 25%. [NOTEThe relative retention times for benzothiadiazine related compound A, chlorothiazide, hydrochlorothiazide, 5-chlorohydrochlorothiazide, and hydrochlorothiazide dimer [6-chloro-N-[(6-chloro-7- sulfamoyl-2,3-dihydro-4H-1,2,4benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4benzothiadiazine-7-sulfonamide 1,1-dioxide] are about 0.5, 0.8, 1.0, 2.1, and 2.6, respectively.]

Chromatograph the Diluent to check for interference by system related peaks. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the relative retention times are about 0.5 for benzothiadiazine related compound A, 0.8 for chlorothiazide, and 1.0 for hydrochlorothiazide; the resolution, R, between benzothiadiazine related compound A and chlorothiazide is not less than 2.0 and the resolution, R, between chlorothiazide and hydrochlorothiazide is not less than 1.5; and the tailing factor for the benzothiadiazine related compound A,

Hydrochlorothiazide / Ofcial Monographs

USP 30

chlorothiazide, and hydrochlorothiazide peaks is not more than 1.5. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 1.0%. ProcedureSeparately inject equal volumes (about 10 mL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for

the hydrochlorothiazide peaks. Calculate the quantity, in mg, of C7H8ClN3O4S2 in the portion of Hydrochlorothiazide taken by the formula: 100C(rU / rS) in which C is the concentration, in mg per mL, of USP Hydrochlorothiazide RS in the Standard preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.