Atenolol and Chlorthalidone Tablets

» Atenolol and Chlorthalidone Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amounts of atenolol (C14H22N2O3) and chlorthalidone (C14H11ClN2O4S).

Packaging and storage— Preserve in well-closed containers.

—

USP Atenolol RS

USP Chlorthalidone RS

Identification—

A: Shake a quantity of powdered Tablets, equivalent to about 50 mg of chlorthalidone, with 5 mL of methanol for 15 minutes, and filter. Apply 10 µL of this test solution, 10 µL of a Standard solution of USP Chlorthalidone RS in methanol containing 10 mg per mL, and 10 µL of a second Standard solution of USP Atenolol RS in methanol containing 10J mg per mL, J being the ratio of the labeled amount, in mg, of atenolol to the labeled amount, in mg, of chlorthalidone per Tablet to a thin-layer chromatographic plate (see Chromatography

621

) coated with a 0.25-mm layer of chromatographic silica gel mixture. Allow the spots to dry, and develop the chromatogram in a solvent system consisting of a mixture of n-butyl alcohol and 1 N ammonium hydroxide (5:1) until the solvent front has moved about three-fourths of the length of the plate. Remove the plate from the developing chamber, and air-dry. Locate the spots on the plate by viewing under short-wavelength UV light: the principal spots obtained from the test solution correspond in RF value, size, and intensity to those obtained from the respective Standard solutions.

B: The retention times of the major peaks in the chromatogram of the Assay preparation correspond to those in the chromatogram of the Standard preparation, as obtained in the Assay.

Dissolution

711

—

Medium: 0.01 N hydrochloric acid; 900 mL.

Apparatus 2: 50 rpm.

Time: 45 minutes.

Determine the amounts of atenolol (C14H22N2O3) and chlorthalidone (C14H11ClN2O4S) dissolved by employing the following method.

Mobile phase and Chromatographic system— Prepare as directed in the Assay.

Diluent— Prepare a mixture of 1000 mL of acetonitrile and 32 mL of 3.6 N sulfuric acid.

Standard solvent— Prepare a mixture of water and Diluent (750: 225).

Standard solution— Dissolve accurately weighed quantities of USP Atenolol RS and USP Chlorthalidone RS in Standard solvent to obtain a solution having known concentrations of about 0.00085L mg of USP Atenolol RS and 0.00085L¢ mg of USP Chlorthalidone RS per mL, L and L¢ being the labeled amounts, in mg, of atenolol and chlorthalidone, respectively, per Tablet.

Test solution— Mix 10.0 mL of the filtered solution under test and 3.0 mL of Diluent.

Procedure— Separately inject equal volumes (about 10 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantities, in mg, of atenolol (C14H22N2O3) and chlorthalidone (C14H11ClN2O4S) dissolved by the same formula:

1170C(rU / rS)

in which C is the concentration, in mg per mL, of the appropriate Reference Standard in the Standard solution; and rU and rS are the responses of the corresponding analyte obtained from the Test solution and the Standard solution, respectively.

Tolerances— Not less than 80% (Q) of the labeled amount of atenolol (C14H22N2O3) is dissolved in 45 minutes, and not less than 70% (Q) of the labeled amount of chlorthalidone (C14H11ClN2O4S) is dissolved in 45 minutes.

Uniformity of dosage units

905

: meet the requirements.

Procedure for content uniformity— Proceed as directed in the Assay, except to prepare the Assay preparation as follows. Transfer 1 Tablet to a volumetric flask of such capacity that when filled to volume, a concentration of about 0.25 mg of chlorthalidone per mL is obtained. Add a mixture of water and acetonitrile (1:1) to about half the capacity of the flask, and shake by mechanical means for not less than 15 minutes to disintegrate the Tablet. Dilute with water to volume, and mix. Pass a portion of this solution through a filter having a 0.5-µm or finer porosity, and use the filtrate as the Assay preparation. Calculate the quantities, in mg, of atenolol (C14H22N2O3) and chlorthalidone (C14H11ClN2O4S) in the Tablet taken by the formula:

CV(rU / rS)

in which V is the volume, in mL, of the volumetric flask used to prepare the Assay preparation; and the other terms are as defined in the Assay.

Assay—

Mobile phase— Prepare a mixture of 740 mL of water, 250 mL of acetonitrile, 8 mL of 3.6 N sulfuric acid, and 930 mg of sodium octyl sulfate. Make adjustments if necessary (see System Suitability under Chromatography

621

Standard preparation— Dissolve accurately weighed quantities of USP Atenolol RS and USP Chlorthalidone RS in a mixture of water and acetonitrile (3:1) to obtain a solution having known concentrations of about 0.25 mg of USP Chlorthalidone RS and 0.25J mg of USP Atenolol RS per mL, J being the ratio of the labeled amount, in mg, of atenolol to the labeled amount, in mg, of chlorthalidone per Tablet.

Assay preparation— Transfer 10 Tablets to a volumetric flask of such capacity that when filled to volume, a concentration of about 0.5 mg of chlorthalidone per mL is obtained. Add a mixture of water and acetonitrile (1:1) to about half the capacity of the flask, and shake by mechanical means for not less than 15 minutes to disintegrate the Tablets. Dilute with a mixture of water and acetonitrile (1:1) to volume, and mix. Pass a portion of this stock solution through a filter having a 0.5-µm or finer porosity. Transfer 25.0 mL of the clear filtrate to a 50-mL volumetric flask, dilute with water to volume, and mix.

Chromatographic system (see Chromatography

621

)— The liquid chromatograph is equipped with a 275-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.7 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative retention times are about 0.8 for atenolol and 1.0 for chlorthalidone; the resolution, R, between the atenolol and chlorthalidone peaks is not less than 3.0; and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 10 µL) of the Assay preparation and the Standard preparation into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the quantities, in mg, of atenolol (C14H22N2O3) and chlorthalidone (C14H11ClN2O4S) in each Tablet taken by the formula:

2C(V/10)(rU / rS)

in which C is the concentration, in mg per mL, of the appropriate USP Reference Standard in the Standard preparation; V is the volume, in mL, of the volumetric flask used to prepare the stock solution for the Assay preparation; and rU and rS are the responses for the corresponding analyte obtained from the Assay preparation and the Standard preparation, respectively.

[note—If a trailing peak or shoulder is observed on the chlorthalidone peak with a relative retention time of not more than 1.1 in the chromatograms of both the Standard preparation and the Assay preparation, sum the areas for the chlorthalidone peak with the trailing peak or shoulder to report the peak responses for chlorthalidone. ]

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
711	Margareth R.C. Marques, Ph.D. Senior Scientific Liaison 1-301-816-8106	(GCDF2010) General Chapters - Dosage Forms

USP35–NF30 Page 2262

Pharmacopeial Forum: Volume No. 29(3) Page 606