Trichlormethiazide

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₈H₈Cl₃N₃O₄S₂          380.64 _{(USP 1-Dec-2022)}

2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3-(dichloromethyl)-3,4-dihydro-, 1,1-dioxide, (±)-; (RS) _{(USP 1-Dec-2022)} -6-Chloro-3-(dichloromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide CAS RN: 133-67-5. UNII: Q58C92TUN0

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1 DEFINITION

Trichlormethiazide (USP 1-Dec-2022) contains NLT 98.0% and NMT 102.0% of trichlormethiazide (C₈H₈Cl₃N₃O₄S₂) calculated on the dried basis _{(USP 1-Dec-2022)}

2 IDENTIFICATION

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A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197M or 197A _{(USP 1-Dec-2022)}

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B. The retention time of the trichlormethiazide peak from the Sample solution corresponds to that of the Standard solution, as obtained in the Assay _{(USP 1-Dec-2022)}

3 ASSAY

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PROCEDURE

Mobile phase: Methanol and 0.05 M monobasic potassium phosphate (30:70)

Internal standard solution: 2.4 mg/ml. of methylparaben in methanol

Standard solution: 0.5 mg/mL of USP Trichlormethiazide RS prepared as follows. Transfer 25 mg of USP Trichlormethiazide RS into a 50-mL volumetric flask. Add 4.0 mL of Internal standard solution, and dilute with methanol to volume.

Sample solution: 0.5 mg/mL of Trichlormethiazide prepared as follows. Transfer 25 mg of Trichlormethiazide into a 50-mL volumetric flask. Add 4.0 mL of Internal standard solution, and dilute with methanol to volume. _{(USP 1-Dec-2022)}

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm x 30-cm; 10-µm _{(USP 1-Dec-2022)} Packing L1

Flow rate: 2.3 mL/min

Injection volume: 420 µL

Run time: NLT 5 times the retention time of the trichlormethiazide peak _{(USP 1-Dec-2022)}

System suitability

Sample: Standard solution

[NOTE-The relative retention times for trichlormethiazide and methylparaben are 0.56 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between the trichlormethiazide _{(USP 1-Dec-2022)} and methylparaben _{(USP 1-Dec-2022)} peaks

Relative standard deviation: NMT 0.73% for peak response ratios _{(USP 1-Dec-2022)}

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of trichlormethiazide (C₈H₈Cl₃N₃O₄S₂) in the portion of Trichlormethiazide taken:

Result = (R_u /R_s ) × (C_s /C_u ) × 100

R_u = peak response ratio of trichlormethiazide to methylparaben from the Sample solution

R_s = peak response ratio of trichlormethiazide to methylparaben from the Standard solution

C_s = concentration of USP Trichlormethiazide RS in the Standard solution (mg/mL)

C_u = concentration of Trichlormethiazide in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the dried basis _{(USP 1-Dec-2022)}

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1%

Delete the following:

Selenium (291) A _{(USP 1-Dec-2022)}

ORGANIC IMPURITIES, DIAZOTIZABLE SUBSTANCES

Standard solution: 250 µg/mL of USP Benzothiadiazine Related Compound A RS in a mixture of toluene and alcohol (50:50)

Sample solution: 10 mg/mL of Trichlormethiazide prepared as follows. Transfer 100.0 mg of Trichlormethiazide into a 10-mL volumetric flask. Dissolve in 1 mL of acetone, and dilute with a mixture of toluene and alcohol (50:50) to volume.

Chromatographic system

(See Chromatography (621), General Procedures, Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 5 µL

Developing solvent system: Ethyl acetate

Spray reagent 1: A solution (1 in 20) of sodium nitrite in dilute hydrochloric acid (1 in 12)

Spray reagent 2: A solution (1 in 1000) of N-(1-naphthyl) ethylenediamine dihydrochloride in alcohol

Analysis

Samples: Standard solution and Sample solution

Apply each of the samples separately to the TLC plate. Allow the spots to dry, and develop the chromatogram in the Developing solvent system until the solvent front has moved about three-fourths of the length of the plate. Remove the plate from the developing chamber, mark the solvent front, and allow the solvent to evaporate. Locate the spots on the plate by spraying first with Spray reagent 1 and then with Spray reagent 2.

Acceptance criteria: After 3 min, any spot of the Sample solution, occurring at the R, value corresponding to that produced by the Standard solution, is not greater in size or intensity than the spot of the Standard solution, corresponding to NMT 2.5% of diazotizable substances.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

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USP Reference Standards 〈11〉

USP Benzothiadiazine Related Compound A RS

4-Amino-6-chlorobenzene-1,3-disulfonamide. _{(USP 1-Dec-2022)}

C₆H₈ClN₃O₄S₂          285.72 _{(USP 1-Dec-2022)}

USP Trichlormethiazide RS