Clonidine Hydrochloride and Chlorthalidone Tablets

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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1 DEFINITION

Clonidine Hydrochloride and Chlorthalidone Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of chlorthalidone (C₁₄H₁₁CIN₂O₄S) and NLT 90.0% and NMT 110.0% of the labeled amount of clonidine hydrochloride (C₉H₉CI₂N₃, HCI). 

2 IDENTIFICATION 

A.

Sample solution: Transfer an amount of powdered Tablets, equivalent to 3 mg of clonidine hydrochloride, to a beaker. Add 30 mL of water, stir for 5 min, and pass through a filter of medium pore size into  a sintered-glass funnel. Transfer the filtrate to a separator, add 5 mL of 0.1 N sodium hydroxide, and extract with 20 mL of chloroform, collecting the chloroform extract in a separator. Extract the chloroform phase with 15 mL of 0.01 N hydrochloric acid, collecting the acid extract in a beaker. Remove any residual chloroform from the acid extract by heating on a steam bath..

Acceptance criteria: The UV absorption spectrum of the Sample solution exhibits maxima and minima at the same wavelengths as that of a similar solution of USP Clonidine Hydrochloride RS, concomitantly measured.

B. INFRARED ABSORPTION

Sample: Transfer 10 powdered Tablets to a 50-mL beaker. Add 10 mL of methanol, boil on a steam bath for 5 min, and filter. Add 20 mL of water to the filtrate, and boil on a steam bath for 5 min under a current of air. Cool, with stirring, in ice until crystals form. Filter the crystals, and dry at 105° for 1 h.

Acceptance criteria: The IR absorption spectrum of a Mineral oil dispersion of the Sample exhibits maxima only at the same wavelengths as that of a similar preparation of USP Chlorthalidone RS.

C. The retention times of the chlorthalidone and clonidine hydrochloride peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE  

Buffer: 1 g/L of monobasic ammonium phosphate in water

Mobile phase: Methanol, acetonitrile, and Buffer (100:100:800)

Clonidine hydrochloride standard stock solution: 1500J µg/mL of USP Clonidine Hydrochloride RS in Buffer; J is the ratio of the labeled amount, in mg, of clonidine hydrochloride to the labeled amount, in mg, of chlorthalidone per Tablet.

Standard solution: 150J µg/mL of USP Clonidine Hydrochloride RS and 150 µg/mL of USP Chlorthalidone RS prepared as follows. Transfer 15 mg of USP Chlorthalidone RS to a 100-mL volumetric flask, dissolve in 10 mL of methanol, and add 25 mL of Buffer and 10.0 mL of Clonidine hydrochloride standard stock solution. Dilute with Buffer to volume.

Sample solution: Transfer an amount equivalent to 15 mg of chlorthalidone from powdered Tablets (NLT 20). Add 10 mL of methanol, and sonicate for 5 min. Add 40 mL of Buffer, and sonicate until the solution is free from agglomerates. Allow to cool to ambient temperature, dilute with Buffer to volume, and centrifuge.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 10-cm; packing L7

Flow rate: 2 mL/min

Injection volume: 20 µL

3.3 System suitability

Sample: Standard solution

[NOTE-The relative retention times for clonidine hydrochloride and chlorthalidone are about 0.2 and 1.0, respectively.]

3.4 Suitability requirements

Resolution: NLT 3 between the clonidine hydrochloride and chlorthalidone peaks

Relative standard deviation: NMT 2%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of clonidine hydrochloride (C₂H₂CI₂N HCI) and chlorthalidone (C₁₄H₁, CIN₂OS) in the portion of Tablets taken: 992 3 14 11

            Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of clonidine hydrochloride or chlorthalidone from the Sample solution

r_S = peak response of clonidine hydrochloride or chlorthalidone from the Standard solution

C_S = concentration of USP Clonidine Hydrochloride RS or USP Chlorthalidone RS in the Standard solution (µg/mL)

C_U = nominal concentration of clonidine hydrochloride or chlorthalidone in the Sample solution (µg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

DISSOLUTION (711).

Medium: Water; 900 mL

Apparatus 2: 100 rpm

Time: 60 min

Sample solution: Pipet 20 mL of a centrifuged portion of the solution under test into a 25-mL volumetric flask, and dilute with 0.5% monobasic ammonium phosphate solution to volume. Use the resulting solution as the Sample solution.

Analysis: Proceed as directed in the Assay, making any necessary volumetric adjustments.

Tolerances: NLT 50% (Q) of the labeled amount of chlorthalidone (C,H, CIN₂OS) and NLT 80% (Q) of the labeled amount of clonidine hydrochloride (C,H,CI₂N, HCI) are dissolved.

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements for Content Uniformity with respect to both clonidine hydrochloride and chlorthalidone

5 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers.

USP REFERENCE STANDARDS (11)

USP Chlorthalidone RS

USP Clonidine Hydrochloride RS