Ramipril Capsules

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 

Ramipril Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of C₂₃H₃₂N₂O₅. 

2 IDENTIFICATION 

Change to read: 

A. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U (CN 1-May-2020) Phosphoric acid solution: 30 mL/L of phosphoric acid in water 

Diluent: Acetonitrile and Phosphoric acid solution (2:3) 

Standard solution: 0.2 mg/mL of USP Ramipril RS in Diluent. Sonicate for 1 min, if necessary, for complete dissolution. Sample solution: Use the Sample solution prepared as directed in the Assay. 

Wavelength range: 200–400 nm Path length: 0.1-cm cell 

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 

Procedure 

Buffer: Dissolve 17 g of monobasic potassium phosphate and 11.2 g of sodium perchlorate in 750 mL of water in a 1-L flask. Dilute with water to volume. Adjust with phosphoric acid to a pH of 2.3. 

Solution A: Acetonitrile, Buffer, and water (1:2:2). [Note—Do not filter Solution A.] 

Solution B: Acetonitrile, Buffer, and water (9:10:6). [Note—Do not filter Solution B.] 

Phosphoric acid solution and Diluent: Prepare as directed in Identification test A. 

Mobile phase: Use the gradient table below. 

Standard solution: 0.2 mg/mL of USP Ramipril RS and 0.002 mg/mL of USP Ramipril Related Compound A RS in Diluent Sample stock solution: Transfer the contents of 8 Capsules into each of the flasks as described in Table 1. Add Capsule shells into the flasks. Add acetonitrile per Table 1, and swirl to agitate the contents. Sonicate for 15 min, and mechanically shake for 10 min. Dilute with acetonitrile to volume for Capsule strengths 5.0 and 10 mg only. For 1.25- and 2.5-mg Capsules, use the solution as is without further dilution. [Note—Extracts from the vial cap may result in extraneous peaks.] 

Table 1 

Sample solution: Nominally 0.2 mg/mL of ramipril in Phosphoric acid solution from the Sample stock solution. Pass through a nylon filter of 0.20-µm pore size, and discard the first 2 mL of filtrate. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 215 nm 

Column: 4.6-mm × 15-cm; 5-µm packing L1 with a guard column, packing L1 

Temperature: 60° 

Flow rate: 1.5 mL/min 

Injection size: 50 µL 

System suitability 

Sample: Standard solution Suitability requirements 

Resolution: NLT 2.5 between ramipril and ramipril related compound A 

Tailing factor: NMT 2.5 for the ramipril peak 

Relative standard deviation: NMT 2.0% for the ramipril peak 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of C₂₃H₃₂N₂O₅ based on the label claim, in the portion of Capsules taken: 

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

r_U = peak response of ramipril from the Sample solution 

r_S = peak response of ramipril from the Standard solution 

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

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

F = relative response factor (see Impurity Table) 

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Dissolution 〈711〉 

Medium: 0.1 N hydrochloric acid; 500 mL 

Apparatus 2: 50 rpm, with sinkers. [Note—A suitable sinker is catalog number CAPWHT-02 available from www.QLA-LLC.com.] Time: 30 min 

Standard solution: 0.01 mg/mL of USP Ramipril RS in Medium 

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Phosphoric acid solution: Prepare as directed in Identification test A. 

Mobile phase: Acetonitrile and Phosphoric acid solution (2:3) 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 215 nm 

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

Temperature: 30° 

Flow rate: 1 mL/min 

Injection size: 25 µL 

Suitability requirements 

Sample: Standard solution 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 2.0% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of ramipril dissolved: 

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

r_U = peak response from the Sample solution 

r_S = peak response from the Standard solution 

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

F = relative response factor (see Impurity Table) 

L = label claim (mg/Capsule) 

V = volume of Medium, 500 mL 

Tolerances: NLT 80% (Q) of the labeled amount of ramipril is dissolved. 

Uniformity of Dosage Units 〈905〉: Meet the requirements 

Procedure for content uniformity 

Phosphoric acid solution: Prepare as directed in Identification test A. 

Mobile phase: Acetonitrile and Phosphoric acid solution (2:3). Pass through a nylon filter of 0.45-µm pore size. Standard solution: 0.03 mg/mL of USP Ramipril RS in Mobile phase. Sonicate for 1 min, if not dissolved completely. Sample solution: Transfer the contents of 1 Capsule into a suitable flask as described in Table 2. Add Mobile phase (about 50% of total volume), and sonicate for 25 min. Mechanically shake for 10 min, and dilute with Mobile phase to volume. Further dilute the solution from the 10-mg strength Capsule with Mobile phase, as shown in Table 2. Pass through a nylon filter of 0.20-µm pore size, and discard the first 2 mL of filtrate. 

Table 2 

Chromatographic system: Proceed as directed in the test for Dissolution. 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of C₂₃H₃₂N₂O₅, based on the label claim, in the portion of Capsules taken: 

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

r_U = peak response of ramipril from the Sample solution 

r_S = peak response of ramipril from the Standard solution 

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

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

5 IMPURITIES 

Organic Impurities 

Procedure 

Buffer, Solution A, Solution B, Phosphoric acid solution, Diluent, Standard solution, and Sample solution: Proceed as directed in the Assay. 

Sensitivity solution: 0.1 µg/mL of ramipril in Diluent from the Standard solution 

Chromatographic system: Prepare as directed in the Assay. 

Suitability requirements 

Samples: Standard solution and Sensitivity solution 

Resolution: NLT 2.5 between ramipril and ramipril related compound A, Standard solution 

Tailing factor: NMT 2.5 for the ramipril peak, Standard solution 

Relative standard deviation: NMT 2.0% for the ramipril peak, Standard solution 

Signal-to-noise ratio: NLT 10 for the ramipril peak, Sensitivity solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of each impurity in the portion of Tablets 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 = nominal concentration of ramipril in the Sample solution (mg/mL)

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

F = relative response factor (see Impurity Table) 

Acceptance criteria 

Individual impurities: See Impurity Table. 

Total impurities: NMT 8.0% for Capsule strength 1.25 mg, NMT 7.0% for Capsule strength 2.5 mg, and NMT 6.0% for Capsule strengths 5 mg and 10 mg. [Note—Total impurities include the sum of individual specified and unspecified degradants. Disregard any peak below 0.1%.] 

Impurity Table 

a Disregard this impurity as it is process related and is controlled in the drug substance.

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

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in well-closed containers, and store at controlled room temperature. 

USP Reference Standards 〈11〉 

USP Ramipril RS 

USP Ramipril Related Compound A RS 

(2S,3aS,6aS)-1-[(S)2-[[(S)1-(Methoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-octahydrocyclopenta[b]pyrrole-2-carboxylic acid. C₂₃H₃₂N₂O₅ 402.48