Captopril 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)

DOWNLOAD PDF HERE

1 DEFINITION

Captopril and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount each of captopril (C₉H₁₅NO₃S) and hydrochlorothiazide (C₆H₈CIN₃O₄S₂).

2 IDENTIFICATION

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

Add the following:

B. The UV spectra of the hydrochlorothiazide and captopril peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay (USP 1-Dec-2019)

3 ASSAY

Change to read:

PROCEDURE

Mobile phase: Methanol, phosphoric acid, and water (250:0.5:750)

System suitability solution: 0.3 mg/mL each of USP Captopril RS, USP Hydrochlorothiazide RS, and USP Benzothiadiazine Related Compound A RS in Mobile phase

Standard solution: 0.3 mg/mL of USP Hydrochlorothiazide RS and about 0.3J mg/mL of USP Captopril RS in Mobile phase, J being the ratio of the labeled amount of captopril (mg) to the labeled amount of hydrochlorothiazide (mg) per Tablet

Sample solution: Nominally equivalent to 0.3 mg/mL of hydrochlorothiazide prepared as follows. Transfer 15 mg of hydrochlorothiazide from NLT 20 finely powdered Tablets into a 50-mL volumetric flask, and dilute with Mobile phase to volume. Sonicate for 15 min with occasional shaking, and centrifuge.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm. For Identification B, use a diode array detector in the range of 190-400 nm.▲ (USP 1-Dec-2019)

Column: 4.6-mm x 30-cm; 10-µm (USP 1-Dec-2019) Packing L11

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for benzothiadiazine related compound A, hydrochlorothiazide, and captopril are 0.4, 0.5, and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.7 between the void volume and benzothiadiazine related compound A; NLT 1.8 between benzothiadiazine related compound A and hydrochlorothiazide; and NLT 2.0 between captopril and hydrochlorothiazide, System suitability solution

Relative standard deviation: NMT 3.0% for both the hydrochlorothiazide and captopril peaks. (USP 1-Dec-2019) Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of captopril (C₉H₁₅NO₃S) and hydrochlorothiazide (C₆H₈CIN₃O₄S₂) in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

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

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

C_U = concentration of USP Captopril RS or USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

C_S = nominal concentration of captopril or hydrochlorothiazide in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Medium: 0.1 N bydrochloric acid: 900 mL

Apparatus 1: 50 rpm

Times

Captopril: 20 min

Hydrochlorothiazide: 30 min

Standard solution: Known concentrations of USP Captopril RS and USP Hydrochlorothiazide RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium, if necessary, to a concentration similar to that of the Standard solution.

Chromatographic system and System suitability (USP 1-Dec-2019): Proceed as directed in the Assay.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of captopril (C₉H₁₅NO₃S) and hydrochlorothiazide (C₆H₈CIN₃O₄S₂) dissolved:

Result = (r_U/r_S) x (C_S/L) x V x D x 100

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

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

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

L = label claim of captopril or hydrochlorothiazide (mg/Tablet)

V = volume of Medium, 900 mL

D = dilution factor for the Sample solution (USP 1-Dec-2019)

Tolerances: NLT 80% (Q) of the labeled amount of captopril (C₉H₁₅NO₃S) and NLT 60% (Q) of the labeled amount of hydrochlorothiazide (C₆H₈CIN₃O₄S₂) are dissolved.

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

5 IMPURITIES

Change to read:

5.1 LIMIT OF CAPTOPRIL DISULFIDE

Mobile phase: Methanol, phosphoric acid, and water (450:0.5:550)

System suitability solution: 0.0075 mg/mL each of USP Captopril RS and USP Hydrochlorothiazide RS, and 0.015 mg/mL of USP Captopril Disulfide RS in Mobile phase

Standard solution: 0.015 mg/ml. of USP Captopril Disulfide RS in Mobile phase

Sample solution: Nominally equivalent to 0.5 mg/mL of captopril prepared as follows. Transfer 25 mg of captopril from NLT 20 finely powdered Tablets into a 50-mL volumetric flask, add about 20 ml. of Mobile phase, and sonicate for 15 min with occasional shaking. Dilute with Mobile phase to volume, and centrifuge. Use the clear supernatant.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 30-cm; 10-µm (USP 1-Dec-2019) packing 11.1

Flow rate: 2 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for hydrochlorothiazide, (USP 1-Dec-2019) captopril, and captopril disulfide are 0.2. (USP 1-Dec-2019) 0.3. and 1.0, respectively.

Suitability requirements

Resolution: NLT 4.0 between captopril and captopril disulfide. Both peaks are resolved from hydrochlorothiazide, System suitability solution.

Relative standard deviation: NMT 3.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of captopril disulfide in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of captopril disulfide from the Sample solution

r_S = peak response of captopril disulfide from the Standard solution

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

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

Acceptance criteria: NMT 3.0%

5.2 LIMIT OF BENZOTHIADIAZINE RELATED COMPOUND A

Mobile phase, System suitability solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the

Assay

Standard solution: 0.01 mg/mL of USP Benzothiadiazine Related Compound A RS in Mobile phase

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of benzothiadiazine related compound A in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of benzothiadiazine related compound A from the Sample solution

r_S = speak response of benzothiadiazine related compound A from the Standard solution

C_S = concentration of USP Benzothiadiazine Related Compound A RS in the Standard solution (mg/mL) 

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

Acceptance criteria: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Change to read:

PACKAGING AND STORAGE: Preserve in tight containers. Store at controlled room temperature. (USP 1-Dec-2019)

Change to read:

USP REFERENCE STANDARDS (11)

USP Benzothiadiazine Related Compound ARS

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

C₆H₈CIN₃O₄S₂   285.73

USP Captopril RS

USP Captopril Disulfide RS

(2'S)-[(25,2'S)-3,3'-Disulfanediylbis(2-methylpropanoyl)]di-L-proline. (USP 1-Dec-2019)

C₁₈H₂₈N₂O₆S₂ 432.55

USP Hydrochlorothiazide RS