Printed on: Fri Jan 05 2024, 08:53:09 PM(EST) Status: Currently Official on 06-Jan-2024 DocId: GUID-1D5879D0-FBF2-4C6F-B8F6-01FF1DA0C880_2_en-US

Printed by: USP NF Official Date: Official as of 01-May-2020 Document Type: USP @2024 USPC
Do Not Distribute DOI Ref: i0bnd DOI: https://doi.org/10.31003/USPNF_M2993_02_01
1

CS = concentration of USP Ramipril RS in the Standard

Ramipril Tablets solution (mg/mL)
DEFINITION CU = nominal concentration of ramipril in the Sample
Ramipril Tablets contain NLT 90.0% and NMT 105.0% of the solution (mg/mL)
labeled amount of ramipril (C23H32N2O5).
Acceptance criteria: 90.0%–105.0%
IDENTIFICATION PERFORMANCE TESTS
Change to read: • DISSOLUTION á711ñ
Medium: 0.1 N hydrochloric acid; 500 mL
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, Infrared Apparatus 2: 50 rpm
Spectroscopy: 197A or 197K▲ (CN 1-May-2020) Time: 30 min
Sample: Finely powder a suitable number of Tablets and Standard stock solution: 0.25 mg/mL of USP Ramipril RS in
transfer a portion of the powder, equivalent to 100 mg of methanol
ramipril, to a suitable beaker. Add 25 mL of methanol, shake Standard solution: (L/500) mg/mL of USP Ramipril RS in
to dissolve, and pass through the filter. Evaporate the Medium from the Standard stock solution where L is the label
solution in air and heat to complete dryness at 105° for 1 h. claim of ramipril in mg/Tablet
Acceptance criteria: Meet the requirements Sample solution: Pass a portion of the solution under test
• B. The retention time of the major peak of the Sample through a suitable filter of 0.45-µm pore size.
solution corresponds to that of the Standard solution, as Solution A, Solution B, Mobile phase, Chromatographic
obtained in the Assay. system, and System suitability: Proceed as directed in the
Assay except for the Injection volume.
ASSAY Injection volume: 100 µL

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• PROCEDURE Analysis
Solution A: 2 g of sodium perchlorate in a mixture of 0.5 mL Samples: Standard solution and Sample solution
of triethylamine and 800 mL of water. Adjust with Calculate the percentage of the labeled amount of ramipril
phosphoric acid to a pH of 3.6, and add 200 mL of (C23H32N2O5) dissolved:
acetonitrile.
Solution B: 2 g of sodium perchlorate in a mixture of 0.5 mL
of triethylamine and 300 mL of water. Adjust with
phosphoric acid to a pH of 2.6, and add 700 mL of
acetonitrile.
ci rU
rS
Result = (rU/rS) × CS × V × (1/L) × 100

= peak response from the Sample solution

= peak response from the Standard solution
Mobile phase: Solution A and Solution B (60:40)
CS = concentration of USP Ramipril RS in the Standard
Diluent: 6.8 g of monobasic sodium phosphate in 500 mL
ffi
solution (mg/mL)
of water. Add 1000 mL each of methanol and acetonitrile.
V = volume of Medium, 500 mL
Adjust with phosphoric acid to a pH of 5.5.
L = label claim for ramipril (mg/Tablet)
Standard solution: 0.1 mg/mL of USP Ramipril RS in Diluent
Sample stock solution: Nominally 0.25 mg/mL of ramipril Tolerances: NLT 80% (Q) of the labeled amount of ramipril
from NLT 10 Tablets prepared as follows. Add 50% of the (C23H32N2O5) is dissolved.
final volume of Diluent to the flask and sonicate to disperse
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• UNIFORMITY OF DOSAGE UNITS á905ñ: Meet the

the Tablets. Sonicate for an additional 30 min and dilute
requirements
with Diluent to volume.
Sample solution: Nominally 0.1 mg/mL of ramipril from the IMPURITIES
Sample stock solution in Diluent. Pass through a suitable filter • ORGANIC IMPURITIES
of 0.45-µm pore size. Solution A and Solution B: Prepare as directed in the Assay.
Chromatographic system Mobile phase: See Table 1.
(See Chromatography á621ñ, System Suitability.)
Mode: LC Table 1
Detector: UV 210 nm Time Solution A Solution B
Column: 4.6-mm × 15-cm; 5-µm packing L1 (min) (%) (%)
Column temperature: 50°
0 70 30
Flow rate: 1 mL/min
Injection volume: 10 µL 6 70 30
Run time: 15 min
30 30 70
System suitability
Sample: Standard solution 40 30 70
Suitability requirements
45 70 30
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0% 50 70 30
Analysis
Samples: Standard solution and Sample solution System suitability solution: 50 µg/mL each of USP
Calculate the percentage of the labeled amount of ramipril Ramipril RS, USP Ramipril Related Compound A RS, and USP
(C23H32N2O5) in the portion of Tablets taken: Ramipril Related Compound D RS in Solution B
Sensitivity solution: 1 µg/mL of USP Ramipril RS in
Result = (rU/rS) × (CS/CU) × 100 Solution B
Standard solution: 0.005 mg/mL of USP Ramipril RS in
rU = peak response of ramipril from the Sample solution Solution B
rS = peak response of ramipril from the Standard Sample solution: Nominally 1 mg/mL of ramipril prepared
solution as follows. Finely powder NLT 20 Tablets and transfer a
portion of the powder to an appropriate volumetric flask.

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Printed on: Fri Jan 05 2024, 08:53:09 PM(EST) Status: Currently Official on 06-Jan-2024 DocId: GUID-1D5879D0-FBF2-4C6F-B8F6-01FF1DA0C880_2_en-US
Printed by: USP NF Official Date: Official as of 01-May-2020 Document Type: USP @2024 USPC
Do Not Distribute DOI Ref: i0bnd DOI: https://doi.org/10.31003/USPNF_M2993_02_01
2

Add about 60% of the flask volume of Solution A, and Signal-to-noise ratio: NLT 10, Sensitivity solution
sonicate for 30 min with intermittent shaking to dissolve. Analysis
Dilute with Solution A to volume. Pass a portion of the Samples: Standard solution and Sample solution
solution through a suitable filter of 0.45-µm pore size. Calculate the percentage of each degradation product in
Chromatographic system the portion of Tablets taken:
(See Chromatography á621ñ, System Suitability.)
Mode: LC Result = (rU/rS) × (CS/CU) × (1/F) × 100
Detector: UV 210 nm
Column: 4.0-mm × 25-cm; 3-µm packing L1 rU = peak response of each degradation product
Column temperature: 65° from the Sample solution
Flow rate: 1 mL/min rS = peak response of ramipril from the Standard
Injection volume: 10 µL solution
System suitability CS = concentration of USP Ramipril RS in the Standard
Samples: System suitability solution, Sensitivity solution, and solution (mg/mL)
Standard solution CU = nominal concentration of ramipril in the Sample
Suitability requirements solution (mg/mL)
Resolution: NLT 3.0 between ramipril related F = relative response factor (see Table 2)
compound A and ramipril, System suitability solution
Relative standard deviation: NMT 5.0%, Standard Acceptance criteria: See Table 2. Disregard any peak less
solution than 0.04%.

Table 2

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Acceptance Acceptance
Relative Relative Criteria for Criteria for 2.5-, 5-, and
Retention Response 1.25-mg Tablets, 10-mg Tablets,
Name Time Factor NMT (%) NMT (%)

Ramipril related compound Aa 0.71 ci — — —

Ramipril 1.0 — — —

Ramipril isopropyl estera, b

1.31 — — —

Hexahydroramiprila, c 1.63 — — —
d
Ramipril related compound D 1.92 0.91 8.0 6.0
ffi
Any unspecified degradation product — 1.0 0.2 0.2

Total degradation products — — 1.0 1.0

a This is a process impurity monitored in the drug substance that is for identification only. It is not included in the total degradation products.
b (2S,3aS,6aS)-1-[(S)2-[[(S)-1-(Methylethoxy)carbonyl-3-phenylpropyl]amino]-1-oxopropyl]-octahydrocyclopenta[b]pyrrole-2-carboxylic acid.
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c Ethyl (2S)2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-dioxodecahydro-1H-cyclopenta[e]pyrrolo[1,2-a]pyrazin-2-yl]-4-phenyl-butanoate.
d Not included in the total degradation products.

ADDITIONAL REQUIREMENTS USP Ramipril Related Compound D RS

• PACKAGING AND STORAGE: Preserve in well-closed Ethyl (2S)2-[(3S,5aS,8aS,9aS)-3-methyl-1,4-
containers, and store at controlled room temperature. dioxodecahydro-1H-cyclopenta[e]pyrrolo[1,2-a]
• USP REFERENCE STANDARDS á11ñ pyrazin-2-yl]-4-phenyl-butanoate.
USP Ramipril RS C23H30N2O4 398.50
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.
C22H30N2O5 402.48

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