Metoprolol Tartrate and Hydrochlorothiazide 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

Metoprolol Tartrate and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of metoprolol tartrate [(C₁₂H₂₅NO₃)₂ · C₄H₆O₆] and hydrochlorothiazide (C₇H₈CIN₃O₄S₂). 

2 IDENTIFICATION

A. The retention times of the metoprolol and hydrochlorothiazide peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The UV spectra of the metoprolol and hydrochlorothiazide peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Solution A: 4.1 g/L of monobasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 3.0.

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile and Solution A (15:85)

Standard solution: 0.1 mg/mL of USP Metoprolol Tartrate RS and 0.05 mg/mL of USP Hydrochlorothiazide RS in Diluent

Sample solution: Nominally 0.1 mg/mL of metoprolol tartrate and 0.05 mg/mL of hydrochlorothiazide in Diluent prepared as follows. Transfer a portion of the powder from NLT 20 finely powdered Tablets to a suitable volumetric flask and dissolve in a suitable amount of Diluent. Sonication may be necessary for complete dissolution. Dilute with Diluent to volume.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 223 nm. For Identification B, use a diode array detector in the range of 200-400 nm.

Column: 4.6-mm x 10-cm; 3.5-µm packing L1

Autosampler temperature: 4°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

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

Suitability requirements

Tailing factor: NMT 2.0 for metoprolol and hydrochlorothiazide

Relative standard deviation: NMT 1.0% for metoprolol and hydrochlorothiazide

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of metoprolol tartrate [(C₁₂H₂₅NO₃)₂ · C₄H₆O₆] and hydrochlorothiazide (C₇H₈CIN₃O₄S₂) in the portion of Tablets taken:

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

r_U = peak response of metoprolol or hydrochlorothiazide from the Sample solution

r_S = peak response of metoprolol or hydrochlorothiazide from the Standard solution

C_S = concentration of USP Metoprolol Tartrate RS or USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

C_U = nominal concentration of the corresponding analyte in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0% of the labeled amount of metoprolol tartrate [(C₁₂H₂₅NO₃)₂ · C₄H₆O₆] and hydrochlorothiazide (C₇H₈CIN₃O₄S₂).

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

Medium: Simulated gastric fluid TS (without enzyme); 900 mL

Apparatus 1: 100 rpm

Time: 30 min

4.1.1 Determination of dissolved metoprolol tartrate

Standard solution: 0.05 mg/mL of USP Metoprolol Tartrate RS in Medium

Sample solution: Remove 125 mL of the solution under test, allow to cool to room temperature, and filter, discarding the first 25 mL of the filtrate. [NOTE-Retain 30 mL of the remaining filtrate of the solution under test for the Determination of dissolved hydrochlorothiazide.] If necessary, prepare 0.05 mg/mL of metoprolol tartrate from the filtrate in fresh Medium.

Instrumental conditions

Mode: UV

Analytical wavelength: 276 nm

Cell: 2 cm

Blank: Medium

Analysis

Samples: Standard solution, Sample solution, and Blank

Transfer to separate separators 50.0 mL each of the Standard solution, Sample solution, and Blank. Add 10 mL of 2.5 N sodium hydroxide to each separator, and extract each with three 15-mL portions of chloroform, filtering the chloroform extracts through pledgets of chloroform-prerinsed glass wool into individual 50-mL volumetric flasks. Dilute the contents of each flask with chloroform to volume, and mix. Determine the absorbances of the solutions obtained.

Calculate the percentage of the labeled amount of metoprolol tartrate [(C₁₂H₂₅NO₃)₂ · C₄H₆O₆] dissolved: 

                      Result = (A_U/ A_S) x C_S x V x D x (100 / L)

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution 

C_S = concentration of USP Metoprolol Tartrate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

D = dilution factor of the Sample solution

L = label claim (mg/Tablet)

4.1.2 Determination of dissolved hydrochlorothiazide

Standard solution: 0.03 mg/mL of USP Hydrochlorothiazide RS in Medium

Sample solution: Pass a portion of the filtrate retained from the Determination of dissolved metoprolol tartrate through a filter of 0.8-µm or finer pore size, and discard the first 5 mL of the filtrate. If necessary, prepare 0.03 mg/mL of hydrochlorothiazide in fresh Medium.

Instrumental conditions

Mode: UV

Analytical wavelength: 316 nm

Cell: 2 cm

Blank: Medium

Analysis

Samples: Standard solution, Sample solution, and Blank

Determine the absorbances of the Standard solution and the Sample solution at the wavelength of maximum absorbance. Calculate the percentage of hydrochlorothiazide [(C₁₂H₂₅NO₃)₂ · C₄H₆O₆] dissolved:

                      Result = (A_U/ A_S) x C_S x V x D x (100 / L)

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

C_S = concentration of USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

D = dilution factor of the Sample solution

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of metoprolol tartrate [(C₁₂H₂₅NO₃)₂ · C₄H₆O₆] and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈CIN₃O₄S₂) is dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905), Content Uniformity

Meet the requirements with respect to metoprolol tartrate and hydrochlorothiazide

5 IMPURITIES

ORGANIC IMPURITIES

Solution A: Dissolve 3.9 g of ammonium acetate in 810 mL of water. Add 2.0 mL of triethylamine, 10.0 mL of glacial acetic acid, and 3.0 mL of phosphoric acid. [NOTE-Adjust the solution to a pH of 3.7 if needed.]

Solution B: Acetonitrile and Solution A (70:30)

Mobile phase: See Table 2.

Table 2

Diluent: Acetonitrile and Solution A (17:83)

System suitability solution: 0.7 µg/mL of USP Maltol RS, 5 µg/mL of USP Benzothiadiazine Related Compound A RS, and 0.5 mg/mL of USP Hydrochlorothiazide RS in Diluent

Standard solution: 10.0 µg/mL of USP Metoprolol Tartrate RS and 2.5 µg/mL of USP Hydrochlorothiazide RS in Diluent

Sensitivity solution: 1.0 µg/mL of USP Metoprolol Tartrate RS and 0.25 µg/mL of USP Hydrochlorothiazide RS in Diluent from the Standard solution

Sample solution: Nominally 1 mg/mL of metoprolol tartrate in Diluent prepared as follows. Transfer a suitable portion of NLT 20 finely powdered Tablets, equivalent to 200 mg of metoprolol tartrate, into a suitable volumetric flask and add Diluent to about 50% of the flask volume. Sonicate for 20 min with occasional swirling. Stir for 15 min. Dilute with Diluent to volume. Centrifuge a portion of the solution. Use the supernatant.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detectors

Metoprolol and related impurities: UV 275 nm

Hydrochlorothiazide and related impurities: UV 320 nm

Column: 4.6-mm x 15-cm; 5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[NOTE-See Table 3 for relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between maltol and benzothiadiazine related compound A; NLT 3.0 between benzothiadiazine related compound A and hydrochlorothiazide, System suitability solution

Relative standard deviation: NMT 5.0% for metoprolol and hydrochlorothiazide, Standard solution

Signal-to-noise ratio: NLT 10 for metoprolol and hydrochlorothiazide, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

For impurities detected at UV 275 nm

Calculate the percentage of maltol and any unspecified degradation product (excluding the peaks that appear at 320 nm) in the portion of

Tablets taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of maltol or any unspecified degradation product from the Sample solution U

r_S = peak response of metoprolol from the Standard solution S

C_S = concentration of USP Metoprolol Tartrate RS in the Standard solution (µg/mL)

C_U = nominal concentration of metoprolol tartrate in the Sample solution (µg/mL)

F = relative response factor (relative to metoprolol)

For impurities detected at UV 320 nm

Calculate the percentage of benzothiadiazine related compound A and any unspecified degradation product (excluding the peaks that appear at 275 nm) in the portion of Tablets taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of benzothiadiazine related compound A or any unspecified degradation product from the Sample solution

r_S = peak response of hydrochlorothiazide from the Standard solution s

C_S = concentration of USP Hydrochlorothiazide RS in the Standard solution (µg/mL)

C_U = nominal concentration of hydrochlorothiazide in the Sample solution (µg/mL)

F = relative response factor (relative to hydrochlorothiazide)

Acceptance criteria: See Table 3. Disregard peaks below 0.1%.

Table 3

^a Not to be included in the total degradation products.

^b Based on the sum of unspecified degradation products determined at 275 nm and at 320 nm.

^c Excluding benzothiadiazine related compound A.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers. Store at controlled room temperature.

USP REFERENCE STANDARDS (11)

USP Benzothiadiazine Related Compound ARS

4-Amino-6-chloro-1,3-benzenedisulfonamide.

C₆H₈OCIN₃O₄S₂           285.73

USP Hydrochlorothiazide RS

USP Maltol RS

3-Hydroxy-2-methyl-4-pyrone.

C₆H₆O₃         126.11

USP Metoprolol Tartrate RS