Ramipril Capsules
DEFINITION
Ramipril Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of C23H32N2O5.
IDENTIFICATION
•  A. Ultraviolet Absorption 197U
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.
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.
Time
(min)
Solution A
(%)
Solution B
(%)
0 100 0
5 100 0
50 0 100
51 0 100
51.1 100 0
60 100 0
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
Strength
of Capsule (mg)
Volumetric
Flask Size (mL)
Acetonitrile
(mL)
1.25 50 25
2.5 100 50
5.0 100 70
10 200 140
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 
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 = (rU/rS) × (CS/CU) × 100
rU== peak response of ramipril from the Sample solution
rS== peak response of ramipril from the Standard solution
CS== concentration of ramipril in the Standard solution (mg/mL)
CU== nominal concentration of ramipril in the Sample solution (mg/mL)
Acceptance criteria:  90.0%–110.0%
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 
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 = (rU/rS) × (CS/L) × V × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of ramipril in the Standard solution (mg/mL)
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
Strength
of Capsule (mg)
Volumetric
Flask Size (mL)
Dilution
Volume
(mL)
Volumetric
Flask
(mL)
1.25 50
2.5 100
5.0 200
10 50 6.0 50
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 = (rU/rS) × (CS/CU) × 100
rU== peak response of ramipril from the Sample solution
rS== peak response of ramipril from the Standard solution
CS== concentration of ramipril in the Standard solution (mg/mL)
CU== concentration of ramipril in the Sample solution (mg/mL)
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 = (rU/rS) × (CS/CU) × 100 × (1/F)
rU== peak response of each individual impurity from the Sample solution
rS== peak response of ramipril from the Standard solution
CU== nominal concentration of ramipril in the Sample solution (mg/mL)
CS== 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
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance Criteria,
NMT (%)
for
1.25-mg
Capsules
Acceptance Criteria,
NMT (%)
for
2.5-mg
Capsules
Acceptance Criteria,
NMT (%)
for
5-mg and 10-mg
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 unspecifed 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).
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in well-closed containers, and store at controlled room temperature.
•  USP Reference Standards 11
USP Ramipril RS Click to View Structure
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
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Sujatha Ramakrishna, Ph.D.
Senior Scientific Liaison
1-301-816-8349
(SM22010) Monographs - Small Molecules 2
711 Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison
1-301-816-8106
(GCDF2010) General Chapters - Dosage Forms
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 4519
Pharmacopeial Forum: Volume No. 35(4) Page 867