Chlorothiazide
(klor'' oh thye' a zide).
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295.732 H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-, 1,1-dioxide.
6-Chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
[58-94-6].» Chlorothiazide contains not less than 98.0 percent and not more than 102.0 percent of C7H6ClN3O4S2, calculated on the dried basis.
Packaging and storage—
Preserve in well-closed containers. Store at 25
, excursions permitted between 15 and 30.
, excursions permitted between 15 and 30.
USP Reference standards 
11
—
11—
USP Benzothiadiazine Related Compound A RS 
4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
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4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
USP Chlorothiazide RS
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Identification—
A:
Infrared Absorption 197M: previously dried at 105 for 1 hour.
197M: previously dried at 105 for 1 hour.
B: Ultraviolet Absorption 197U—
197U—
Solution:
10 µg per mL.
Medium:
sodium hydroxide solution (1 in 250).
Absorptivities at 292 nm, calculated on the dried basis, do not differ by more than 3.0%.
Loss on drying 731—
Dry it at 105 for 1 hour: it loses not more than 1.0% of its weight.
731—
Dry it at 105 for 1 hour: it loses not more than 1.0% of its weight.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Chloride—
Dissolve 1.00 g in a mixture of 10 mL of water and 10 mL of sodium hydroxide solution (1 in 10). Cool in an ice bath, and add 20 mL of water and 5 mL of nitric acid. A flocculent, white precipitate is formed. Titrate potentiometrically with 0.050 N silver nitrate, using a silver–silver chloride electrode system: not more than 0.28 mL is required (0.05%).
Selenium 291:
0.003%.
291:
0.003%.
Heavy metals, Method II 231:
0.001%.
231:
0.001%.
Related compounds—
Mobile phase, Resolution solution, and Chromatographic system—
Proceed as directed in the Assay.
Standard solution—
Dissolve an accurately weighed quantity of USP Benzothiadiazine Related Compound A RS in Mobile phase to obtain a solution having a known concentration of about 1.5 µg per mL.
Test solution—
Proceed as directed for Assay preparation in the Assay.
Procedure—
Separately inject equal volumes (about 20 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. The relative retention times are about 0.9 for benzothiadiazine related compound A and 1.0 for chlorothiazide. Calculate the quantity, in mg, of benzothiadiazine related compound A in the portion of Chlorothiazide taken by the formula:
0.2C(rU / rS)
in which C is the concentration, in µg per mL, of USP Benzothiadiazine Related Compound A RS in the Standard solution; and rU and rS are the peak responses of benzothiadiazine related compound A obtained from the Test solution and the Standard solution, respectively: not more than 1.0% is present.
Assay—
Mobile phase—
Prepare a suitable degassed mixture of 0.1 M monobasic sodium phosphate and acetonitrile (9:1), adjust with phosphoric acid to a pH of 3.0 ± 0.1, and filter. Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Resolution solution—
Dissolve quantities of USP Reference Standards in Mobile phase to obtain solutions having known concentrations of about 0.15 mg per mL of USP Chlorothiazide RS and about 1.5 µg per mL of USP Benzothiadiazine Related Compound A RS.
Standard preparation—
[note—A volume 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 RS in Mobile phase to obtain a solution having a known concentration of about 0.15 mg per mL.
Assay preparation—
Transfer about 30 mg of Chlorothiazide, accurately weighed, to a 200-mL volumetric flask, dissolve in a small volume of acetonitrile, not exceeding 10% of the total volume of the solution, dilute with Mobile phase 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 L1. The flow rate is about 1.2 mL per minute. Chromatograph replicate injections of the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation is not more than 1.5%. Chromatograph the Resolution solution: the resolution, R, between benzothiadiazine related compound A and chlorothiazide is not less than 3.5.
621)—
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 1.2 mL per minute. Chromatograph replicate injections of the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation is not more than 1.5%. Chromatograph the Resolution solution: the resolution, R, between benzothiadiazine related compound A and chlorothiazide is not less than 3.5.
Procedure—
[note—The Standard preparation and the Assay preparation should be injected immediately upon preparation. ] Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major chlorothiazide peaks. The relative retention times are about 0.9 for benzothiadiazine related compound A and 1.0 for chlorothiazide. Calculate the quantity, in mg, of C7H6ClN3O4S2 in the portion of Chlorothiazide taken by the formula:
200C(rU / rS)
in which C is the concentration, in mg per mL, of USP Chlorothiazide RS in the Standard preparation; and rU and rS are the peak responses of chlorothiazide 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 2632
Pharmacopeial Forum: Volume No. 29(5) Page 1439