Captopril

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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C₉H₁₅INO₃S      217.29

L-Proline, 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-;

1-[(2S)-3-Mercapto-2-methylpropionyl]-L-proline CAS RN: 62571-86-2; UNII: 9G64RSX1XD.

1 DEFINITION

Captopril contains NLT 97.5% and NMT 102.0% of captopril (C₉H₁₅INO₃S), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

3 ASSAY

PROCEDURE

Sample solution: Dissolve about 300 mg of Captopril in 100 mL of water in a suitable glass-stoppered fiask. Add 10 mL of 3.6 N sulfuric acid, 1 g of potassium iodide, and 2 mL of starch TS.

Titrimetric system

(See Titrimetry (541).)

Mode: Direct titration

Titrant: Dissolve 3.567 g of potassium iodate, previously dried at 110° to constant weight, in water to make 1.0 L.

Endpoint detection: Visual

Analysis: Titrate with Titrant to a faint blue endpoint that persists for NLT 30 s. Perform a blank determination, and make any necessary correction. Each mL of Titrant is equivalent to 21.73 mg of captopril aptopril (C₉H₁₅INO₃S).

Acceptance criteria: 97.5%-102.0% on the dried basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.2%

ORGANIC IMPURITIES

Use low-actinic glassware to prepare the Standard solution and Sample solution.

Mobile phase: 9-in-100 solution of tetrahydrofuran in methanol and 1-in-2000 solution of phosphoric acid (33:67)

System suitability stock solution: 0.1 mg/ml. each of USP Captopril RS, USP Captopril Disulfide RS, and 3-acetylthio-2-methylpropanoic acid in methanol

System suitability solution: 10 µg/mL each of USP Captopril RS, USP Captopril Disulfide RS, and 3-acetylthio-2-methylpropanoic acid in methanol from System suitability stock solution

Standard solution: 10 µg/mL of USP Captopril Disulfide RS in methanol

Sample solution: 2 mg/mL of Captopril in methanol. Use the solution promptly.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 3.9-mm x 30-cm; packing L1

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

[NOTE-The relative retention times for captopril, 3-acetylthio-2-methylpropanoic acid, and captopril disulfide are 0.32, 0.42, and 1.0, respectively.]

Suitability requirements

Resolution: NLT 3.0 between captopril and 3-acetylthio-2-methylpropanoic acid

Analysis

Samples: Standard solution and Sample solution

Compare the peak responses from the Sample solution, excluding those of the solvent, captopril, and captopril disulfide, with the main peak response from the Standard solution.

Calculate the percentage of captopril disulfide in the portion of Captopril 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 (μg/mL)

C_u = concentration of Captopril in the Sample solution (μg/mL)

Acceptance criteria: NMT 1.0% of captopril disulfide. The peak response of each impurity does not exceed 40% of the main peak response from the Standard solution (0.2%), and the sum of the impurity peak responses does not exceed the main peak response from the Standard solution (0.5%).

5 SPECIFIC TESTS

Optical Rotation, Specific Rotation 〈781S〉

Sample solution: 10 mg/mL in dehydrated alcohol

Acceptance criteria: −125° to −134°

Loss on Drying 〈731〉

Analysis: Dry a sample under vacuum at 60° for 3 h.

Acceptance criteria: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers.

Change to read:

USP Reference Standards 〈11〉

USP Captopril RS

USP Captopril Disulfide RS

(2′S)-[(2S,2′S)-3,3′-Disulfanediylbis(2-methylpropanoyl)]di-l-proline. (ERR 1-Dec-2021)

C₁₈H₂₈N₂O₆S₂    432.55