Ramipril

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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C₂₃H₃₂N₂O₅ 416.52  

Cyclopenta[b]pyrrole-2-carboxylic acid, 1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]octahydro-, [2S-[1[R*(R*)],2α,3aβ,6aβ]]-; (2S,3aS,6aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid, 1-ethyl ester (2S,3aS,6aS)-1-{[(S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl]-L-alanyl}octahydrocyclopenta[b]pyrrole-2-carboxylic acid  CAS RN®:  87333-19-5; UNII: L35JN3I7SJ. 

1 DEFINITION 

Ramipril contains NLT 98.0% and NMT 102.0% of ramipril (C₂₃H₃₂N₂O₅), calculated on the dried basis. 

2 IDENTIFICATION 

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K 

B: The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

3 ASSAY 

Change to read: 

Procedure 

Buffer: 0.1% solution of sodium dodecyl sulfate. Adjust with phosphoric acid to a pH of 2.4 ± 0.1. 

Mobile phase: Acetonitrile and Buffer (45:55). Adjust with phosphoric acid to a pH of 2.75 ± 0.1. 

System suitability solution: 0.2 mg/mL of USP Ramipril RS and 0.01 mg/mL of USP Ramipril Related Compound A RS, in Mobile phase Standard solution: 0.2 mg/mL of USP Ramipril RS in Mobile phase 

Sample stock solution: 1 mg/mL of Ramipril prepared as follows. Dissolve 100 mg of Ramipril in 10 mL of Acetonitrile in a 100-mL volumetric flask, and dilute with Mobile phase to volume. 

Sample solution: 0.2 mg/mL of Ramipril in Mobile phase from Sample stock solution 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 210 nm 

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

Flow rate: 1.8 mL/min 

Injection volume: 20 µL 

Run time: NLT 2 times the retention time of ramipril  

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention time for ramipril related compound A and ramipril are 0.8 and 1.0, respectively.]  Suitability requirements 

Resolution: NLT 2.0 between ramipril and ramipril related compound A, System suitability solution   

Relative standard deviation: NMT 0.73%, Standard solution  

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of ramipril (C₂₃H₃₂N₂O₅) in the portion of Ramipril taken:   

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of ramipril from the Sample solution 

r_S = peak response of ramipril from the Standard solution 

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

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

Acceptance criteria: 98.0%–102.0% on the dried basis 

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.1% 

Delete the following: 

Limit of Palladium 

Diluent: Water and nitric acid (997:3) 

Standard stock solution: Dissolve 50 mg of palladium metal taken in a 100-mL volumetric flask, in 9 mL of hydrochloric acid, and dilute with water to volume. 

Standard solutions: 0.02, 0.03, and 0.05 µg/mL of palladium in Diluent from Standard stock solution 

Sample solution: 2 mg/mL of Ramipril in Diluent 

Blank solution: 1.5 mg/mL of magnesium nitrate in Diluent 

Instrumental conditions 

(See Atomic Absorption Spectroscopy 〈852〉.) 

Mode: Atomic absorption spectrophotometry 

Analytical wavelength: 247.6 nm palladium emission line 

Lamp: Palladium hollow-cathode 

Flame: Air–acetylene 

Injection volume: 20 µL each for the Standard solutions and Sample solution, and 10 µL for the Blank solution Analysis: Concomitantly determine the absorbances of the Standard solutions, Sample solution, and the Blank solution. Plot the absorbances of the Standard solutions versus the concentration, in µg/mL, of palladium, and draw the straight line best fitting the three plotted points. From the graph so obtained, determine the concentration, C_P , in µg/mL, of palladium in the Sample solution. 

Calculate the percentage of palladium in the portion of Ramipril taken: 

Result = (C_P/C_R) × 100 

C_P = concentration of palladium in the Sample solution (µg/mL) 

C_R = concentration of Ramipril in the Sample solution (µg/mL) 

Acceptance criteria: 20 ppm  

Change to read: 

Organic Impurities 

Solution A: 2.0 g of sodium perchlorate in a mixture of 800 mL of water and 0.5 mL of triethylamine. Adjust with phosphoric acid to a pH of about 3.6 ± 0.1, and add 200 mL of acetonitrile. 

Solution B: 2.0 g of sodium perchlorate in a mixture of 300 mL of water and 0.5 mL of triethylamine. Adjust with phosphoric acid to a pH of about 2.6 ± 0.1, and add 700 mL of acetonitrile. 

System suitability solution: 0.5 mg/mL each of USP Ramipril RS, USP Ramipril Related Compound A RS, USP Ramipril Related Compound B RS, USP Ramipril Related Compound C RS, and USP Ramipril Related Compound D RS in Solution B 

Standard solution: 5 µg/mL of USP Ramipril RS in Solution B 

Sensitivity solution: 0.5 µg/mL of USP Ramipril RS in Solution B from Standard solution  

Sample solution: 1 mg/mL of Ramipril in Solution A. Keep the Sample solution cold until injected. 

Mobile phase: See Table 1. 

Table 1 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 210 nm 

Column: 4.0-mm × 25-cm; 3-µm packing L1 

Column temperature: 65° 

Flow rate: 1 mL/min 

Injection volume: 10 µL 

System suitability 

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

[Note—See Table 2 for relative retention times.] 

Suitability requirements 

Resolution: NLT 3.0 between ramipril related compound A and ramipril, System suitability solution 

Relative standard deviation: NMT 5.0% for ramipril, Standard solution 

Signal-to-noise ratio: NLT 10, Sensitivity solution  

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of each specified and any unspecified impurity in the portion of Ramipril taken: 

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

r_U = peak response of each individual impurity from the Sample solution 

r_S = peak response of ramipril from the Standard solution 

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

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

 F = relative response factor (see Table 2) 

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.  

Table 2 

5 SPECIFIC TESTS 

Optical Rotation 〈781S〉, Procedures, Specific Rotation 

Sample solution: 10 mg/mL of Ramipril in 0.1 M methanolic hydrochloric acid 

Acceptance criteria: +32.0° to +38.0°, at 20° 

Loss on Drying 〈731〉 

Analysis: Dry under vacuum at a pressure not exceeding 5 mm of mercury at 60° for 6 h. 

Acceptance criteria: NMT 0.2% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight containers. 

Change to read: 

USP Reference Standards 〈11〉 

USP Ramipril RS 

USP Ramipril Related Compound A RS 

(2S,3aS,6aS)-1-{[(S)-1-carboxy-3-phenylpropyl]-L-alanyl}octahydrocyclopenta[b]pyrrole-2-carboxylic acid.  

C₂₂H₃₀N₂O₅ 402.49  

USP Ramipril Related Compound B RS 

(2S,3aS,6aS)-1-{[(S)-1-Methoxy-1-oxo-4-phenylbutan-2-yl]-L-alanyl}octahydrocyclopenta[b]pyrrole-2-carboxylic acid; Also known as Ramipril isopropylester.  

C₂₄H₃₄N₂O₅ 430.55  

USP Ramipril Related Compound C RS 

(2S,3aS,6aS)-1-{[(S)-4-Cyclohexyl-1-ethoxy-1-oxobutan-2-yl]-L-alanyl}octahydrocyclopenta[b]pyrrole-2-carboxylic acid hydrochloride; Also known as Hexahydroramipril hydrochloride.  

C₂₃H₃₈N₂O₅  · HCl 459.02  

USP Ramipril Related Compound D RS 

Ethyl (S)-2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-dioxodecahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl]-4-phenylbutanoate.  

C₂₃H₃₀N₂O₄  398.50