Accessed from 10.6.1.

1 by merck1 on Sat Jun 20 21:57:28 EDT 2015

USP 38 Official Monographs / Ramipril 5135

[NOTE—Make adjustments at the 75:25 ratio stage, if
necessary, to achieve elution of ramipril 16–19 min af-
ter injection of the Standard solution.]
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 Sample solution
[NOTE—See Table 2 for relative retention times.]
Suitability requirements
Resolution: NLT 3.0 between ramipril related com-
pound A and ramipril, System suitability solution
Tailing factor: 0.8–2.0 for ramipril, Sample solution
Relative standard deviation: NMT 5.0% for ramipril,
Standard solution
Retention time: 16–19 min, Sample solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each specified and any
other impurity in the portion of Ramipril taken:
Acceptance criteria: NMT 0.2%
ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in tight containers.
• 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]-octahydro-
cyclopenta[b]pyrrole-2-carboxylic acid).
C22H30N2O5 402.48
USP Ramipril Related Compound B RS
((2S,3aS,6aS)-1-[(S)2-[[(S)-1-(Methylethoxy)carbonyl-
3-phenylpropyl]amino]-1-oxopropyl]-octahydro-
cyclopenta[b]pyrrole-2-carboxylic acid).
C24H34N2O5 430.54
USP Ramipril Related Compound C RS
(2S,3aS,6aS)-1-[(S)2-[[(S)1-Ethoxycarbonyl-3-cyclohexyl
propyl]amino]-1-oxopropyl]-octahydrocyclopenta
[b]pyrrole-2-carboxylic acid.
C23H38N2O5 422.56
USP Ramipril Related Compound D RS
Ethyl (2S)2-[(3S,5aS,8aS, 9aS)-3-methyl-1,4-diox-
odecahydro-1H-cyclopenta[e]pyrrolo[1,2-a]pyrazin-
2-yl]-4-phenyl-butanoate.
C23H30N2O4 398.50

Result = (rU/rS) × (CS/CU) × (1/F) × 100

rU = response of each individual peak from the .

Sample solution Ramipril Capsules

rS = peak response for ramipril from the Standard
solution DEFINITION
CS = concentration of USP Ramipril RS in the Ramipril Capsules contain NLT 90.0% and NMT 110.0% of
Standard solution (mg/mL) the labeled amount of C23H32N2O5.
CU = concentration of Ramipril in the Sample
solution (mg/mL) IDENTIFICATION
F = relative response factor (see Table 2) • A. ULTRAVIOLET ABSORPTION 〈197U〉

USP Monographs
Acceptance criteria: See Table 2. Phosphoric acid solution: 30 mL/L of phosphoric acid
in water
Table 2 Diluent: Acetonitrile and Phosphoric acid solution (2:3)
Standard solution: 0.2 mg/mL of USP Ramipril RS in
Relative Relative Acceptance Diluent. Sonicate for 1 min, if necessary, for complete
Retention Response Criteria, dissolution.
Name Time Factor NMT (%) Sample solution: Use the Sample solution prepared as
Ramipril related com- directed in the Assay.
pound A 0.8 1.0 0.5 Wavelength range: 200–400 nm
Ramipril 1.0 — — Path length: 0.1-cm cell
Ramipril related com- • B. The retention time of the major peak of the Sample
pound B 1.3 1.0 0.5 solution corresponds to that of the Standard solution, as
Ramipril related com- obtained in the Assay.
pound C 1.5 0.42 0.5
ASSAY
Ramipril related com- • PROCEDURE
pound D 1.6 1.0 0.5 Buffer: Dissolve 17 g of monobasic potassium phos-
Any other individual
— — phate and 11.2 g of sodium perchlorate in 750 mL of
impurity 0.1 water in a 1-L flask. Dilute with water to volume. Adjust
Total impurities — — 1.0 with phosphoric acid to a pH of 2.3.
Solution A: Acetonitrile, Buffer, and water (1:2:2).
[NOTE—Do not filter Solution A.]
SPECIFIC TESTS Solution B: Acetonitrile, Buffer, and water (9:10:6).
• OPTICAL ROTATION, Specific Rotation 〈781S〉 [NOTE—Do not filter Solution B.]
Sample solution: 10 mg/mL, in 0.1 M methanolic hy- Phosphoric acid solution and Diluent: Prepare as di-
drochloric acid rected in Identification test A.
Acceptance criteria: +32.0° to +38.0°, at 20° Mobile phase: Use the gradient table below.
• LOSS ON DRYING 〈731〉
Analysis: Dry under vacuum at a pressure not exceed-
ing 5 mm of mercury at 60° for 6 h. Time Solution A Solution B
(min) (%) (%)
0 100 0
5 100 0
50 0 100
51 0 100

Official from May 1, 2015

Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.
 Accessed from 10.6.1.1 by merck1 on Sat Jun 20 21:57:28 EDT 2015

5136 Ramipril / Official Monographs USP 38

Time Solution A Solution B Sample solution: Pass a portion of the solution under
(min) (%) (%) test through a suitable filter of 0.45-µm pore size.
51.1 100 0 Phosphoric acid solution: Prepare as directed in Identi-
60 100 0 fication test A.
Mobile phase: Acetonitrile and Phosphoric acid solution
Standard solution: 0.2 mg/mL of USP Ramipril RS and (2:3)
0.002 mg/mL of USP Ramipril Related Compound A RS Chromatographic system
in Diluent (See Chromatography 〈621〉, System Suitability.)
Sample stock solution: Transfer the contents of 8 Cap- Mode: LC
sules into each of the flasks as described in Table 1. Add Detector: UV 215 nm
Capsule shells into the flasks. Add acetonitrile per Table Column: 4.6-mm × 15-cm; 5-µm packing L1
1, and swirl to agitate the contents. Sonicate for 15 Temperature: 30°
min, and mechanically shake for 10 min. Dilute with Flow rate: 1 mL/min
acetonitrile to volume for Capsule strengths 5.0 and Injection size: 25 µL
10 mg only. For 1.25- and 2.5-mg Capsules, use the Suitability requirements
solution as is without further dilution. [NOTE—Extracts Sample: Standard solution
from the vial cap may result in extraneous peaks.] Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
Analysis
Table 1
Samples: Standard solution and Sample solution
Strength Volumetric Acetonitrile Calculate the percentage of ramipril dissolved:
of Capsule (mg) Flask Size (mL) (mL)
1.25 50 25 Result = (rU/rS) × (CS/L) × V × 100
2.5 100 50
rU = peak response from the Sample solution
5.0 100 70 rS = peak response from the Standard solution
10 200 140 CS = concentration of ramipril in the Standard
solution (mg/mL)
Sample solution: Nominally 0.2 mg/mL of ramipril in L = label claim (mg/Capsule)
Phosphoric acid solution from the Sample stock solution. V = volume of Medium, 500 mL
Pass through a nylon filter of 0.20-µm pore size, and Tolerances: NLT 80% (Q) of the labeled amount of
discard the first 2 mL of filtrate. ramipril is dissolved.
Chromatographic system • UNIFORMITY OF DOSAGE UNITS 〈905〉: Meet the
(See Chromatography 〈621〉, System Suitability.) requirements
Mode: LC Procedure for content uniformity
Detector: UV 215 nm Phosphoric acid solution: Prepare as directed in Iden-
Column: 4.6-mm × 15-cm; 5-µm packing L1 with a tification test A.
guard column, packing L1 Mobile phase: Acetonitrile and Phosphoric acid solution
USP Monographs

Temperature: 60° (2:3). Pass through a nylon filter of 0.45-µm pore size.
Flow rate: 1.5 mL/min Standard solution: 0.03 mg/mL of USP Ramipril RS in
Injection size: 50 µL Mobile phase. Sonicate for 1 min, if not dissolved com-
System suitability pletely.
Sample: Standard solution Sample solution: Transfer the contents of 1 Capsule
Suitability requirements into a suitable flask as described in Table 2. Add Mobile
Resolution: NLT 2.5 between ramipril and ramipril phase (about 50% of total volume), and sonicate for 25
related compound A min. Mechanically shake for 10 min, and dilute with
Tailing factor: NMT 2.5 for the ramipril peak Mobile phase to volume. Further dilute the solution
Relative standard deviation: NMT 2.0% for the from the 10-mg strength Capsule with Mobile phase, as
ramipril peak shown in Table 2. Pass through a nylon filter of 0.20-
Analysis µm pore size, and discard the first 2 mL of filtrate.
Samples: Standard solution and Sample solution
Calculate the percentage of C23H32N2O5, based on the
label claim, in the portion of Capsules taken: Table 2
Strength Volumetric Dilution Volumetric
Result = (rU/rS) × (CS/CU) × 100 of Capsule Flask Size Volume Flask
(mg) (mL) (mL) (mL)
rU = peak response of ramipril from the Sample 1.25 50 — —
solution
rS = peak response of ramipril from the Standard 2.5 100 — —
solution 5.0 200 — —
CS = concentration of ramipril in the Standard 10 50 6.0 50
solution (mg/mL)
CU = nominal concentration of ramipril in the Chromatographic system: Proceed as directed in the
Sample solution (mg/mL) test for Dissolution.
Acceptance criteria: 90.0%–110.0% Analysis
Samples: Standard solution and Sample solution
PERFORMANCE TESTS Calculate the percentage of C23H32N2O5, based on the
• DISSOLUTION 〈711〉 label claim, in the portion of Capsules taken:
Medium: 0.1 N hydrochloric acid; 500 mL
Apparatus 2: 50 rpm, with sinkers. [NOTE—A suitable Result = (rU/rS) × (CS/CU) × 100
sinker is catalog number CAPWHT-02 available from
www.QLA-LLC.com.] rU = peak response of ramipril from the Sample
Time: 30 min solution
Standard solution: 0.01 mg/mL of USP Ramipril RS in rS = peak response of ramipril from the Standard
Medium solution

Official from May 1, 2015

Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 10.6.1.1 by merck1 on Sat Jun 20 21:57:28 EDT 2015

USP 38 Official Monographs / Ranitidine 5137

CS = concentration of ramipril in the Standard

solution (mg/mL) ADDITIONAL REQUIREMENTS
CU = concentration of ramipril in the Sample • PACKAGING AND STORAGE: Preserve in well-closed con-
solution (mg/mL) tainers, and store at controlled room temperature.
• USP REFERENCE STANDARDS 〈11〉
IMPURITIES USP Ramipril RS
Organic Impurities USP Ramipril Related Compound A RS
• PROCEDURE (2S,3aS,6aS)-1-[(S)2-[[(S)1-(Methoxycarbonyl)-3-phenyl-
Buffer, Solution A, Solution B, Phosphoric acid propyl]amino]-1-oxopropyl]-octahydrocyclopenta
solution, Diluent, Standard solution, and Sample so- [b]pyrrole-2-carboxylic acid.
lution: Proceed as directed in the Assay. C22H30N2O5 402.48
Sensitivity solution: 0.1 µg/mL of ramipril in Diluent
from the Standard solution
Chromatographic system: Prepare as directed in the
Assay.
Suitability requirements
Ranitidine Hydrochloride
.

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, Stan-
dard solution
Relative standard deviation: NMT 2.0% for the
ramipril peak, Standard solution C13H22N4O3S · HCl 350.86
Signal-to-noise ratio: NLT 10 for the ramipril peak, 1,1-Ethenediamine, N-[2-[[[5-[(dimethylamino)methyl]-
Sensitivity solution 2-furanyl]-methyl]thio]ethyl]-N′-methyl-2-nitro-,
Analysis monohydrochloride.
Samples: Standard solution and Sample solution N-[2-[[[5-[(Dimethylamino)methyl]-
Calculate the percentage of each impurity in the por- 2-furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-
tion of Tablets taken: ethenediamine, hydrochloride [66357-59-3].
Result = (rU/rS) × (CS/CU) × 100 × (1/F) » Ranitidine Hydrochloride contains not less
than 97.5 percent and not more than 102.0 per-
rU
= peak response of each individual impurity
from the Sample solution cent of C13H22N4O3S · HCl, calculated on the
rS = peak response of ramipril from the Standard dried basis.
solution
CU = nominal concentration of ramipril in the Packaging and storage—Preserve in tight, light-resistant
Sample solution (mg/mL) containers.

USP Monographs
CS = concentration of ramipril in the Standard USP Reference standards 〈11〉—
solution (mg/mL) USP Ranitidine Hydrochloride RS
F = relative response factor (see Impurity Table) USP Ranitidine Resolution Mixture RS
Acceptance criteria It is a mixture of ranitidine hydrochloride and four re-
Individual impurities: See Impurity Table. lated impurities: ranitidine-N-oxide, ranitidine complex
Total impurities: NMT 8.0% for Capsule strength nitroacetamide, ranitidine diamine hemifumarate, and
1.25 mg, NMT 7.0% for Capsule strength 2.5 mg, ranitidine amino alcohol hemifumarate.
and NMT 6.0% for Capsule strengths 5 mg and Ranitidine-N-oxide: N,N-dimethyl[5-[[[2-[[1-(methyl-
10 mg. [NOTE—Total impurities include the sum of in- amino)-2-nitroethenyl]amino]ethyl]sulphanyl]meth-
dividual specified and unspecified degradants. Disre- yl]furan-2-yl]methanamine N-oxide.
gard any peak below 0.1%.]
Impurity Table
Acceptance Acceptance Acceptance
Criteria, Criteria, Criteria,
NMT (%) NMT (%) NMT (%)
Relative Relative for for for
Retention Response 1.25-mg 2.5-mg 5-mg and 10-mg
Name Time Factor Capsules Capsules Capsules
Ramipril diacid 0.24 0.41 1.0 1.0 1.0
Ramipril related compound
Aa . 0.72 — — — —
Ramipril diacid impuritya . 0.85 — — — —
Ramipril 1 — — — —
Ramipril related compound
Ba . 1.31 — — — —
Ramipril related compound
Ca . 1.68 — — — —
Ramipril related compound
Db . 1.84 1 8.0 5.5 5.0
Any other individual un-
specifed degradant — — 0.2 0.2 0.2
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).
.

Official from May 1, 2015

Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.