Fosinopril Sodium
(fos in' oh pril soe' dee um).
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C30H45NNaO7P 585.64
l-Proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-, sodium salt, [1[S*(R*)],2,4]-;    
(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt     [88889-14-9].
DEFINITION
Fosinopril Sodium contains NLT 97.5% and NMT 102.0% of C30H45NNaO7P, calculated on the anhydrous basis.
IDENTIFICATION
ASSAY
•  Procedure
Mobile phase:  Acetonitrile, phosphoric acid, and water (2000:1:10)
System suitability solution:  0.1 mg/mL of USP Fosinopril Sodium RS and 0.01 mg/mL of USP Fosinopril Related Compound B RS in Mobile phase
Standard solution:  0.10 mg/mL of USP Fosinopril Sodium RS in Mobile phase
Sample solution:  0.10 mg/mL of Fosinopril Sodium in Mobile phase
Chromatographic system  
Mode:  LC
Detector:  UV 214 nm
Column:  3.9-mm × 15-cm; packing L3
Temperature:  33
Flow rate:  1.2 mL/min
Injection size:  20 µL
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 2.0 between fosinopril related compound B and fosinopril sodium
Relative standard deviation:  NMT 2.0% for Fosinopril peak
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of C30H45NNaO7P in the portion of Fosinopril Sodium taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Fosinopril Sodium RS in the Standard solution (mg/mL)
CU== nominal concentration of Fosinopril Sodium in the Sample solution (mg/mL)
Acceptance criteria:  97.5%–102.0% on the anhydrous basis
IMPURITIES
Inorganic Impurities 
Organic Impurities 
•  Procedure 1
Mobile phase, Sample solution and Chromatographic system:  Proceed as directed in the Assay. [Note—Record the chromatograms for four times the retention time of the fosinopril sodium peak. ]
System suitability solution:  0.1 mg/mL of USP Fosinopril Sodium RS and 0.01 mg/mL each of USP Fosinopril Related Compound A RS and USP Fosinopril Related Compound B RS in Mobile phase
Analysis 
Sample:  Sample solution
Calculate the percentage of each individual related compound:
Result = (rU/rT) × 100
rU== individual peak response, other than the fosinopril sodium peak
rT== sum of all the peak responses
[Note—If present, two more diastereomers may not be resolved from fosinopril related compound B by this method. These peaks, appearing at a relative retention time of 0.7, should be integrated together to determine conformance with the limit in Impurity Table 1. ]
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Impurity Table 1
Name Relative
Retention
Time
Procedure Acceptance
Criteria,
NMT (%)
Fosinopril Related Compound Aa 2.0 1 0.75
Fosinopril Related Compound Bb 0.7 1 1.0
Fosinopril Related Compound Cc 1.2 2 0.3
Fosinopril Related Compound Dd 1.3 2 0.3
Fosinopril Related Compound Ee 0.8 3 0.3
Fosinopril Related Compound Ff 0.9 3 0.3
Impurity 1g 0.53 1 0.3
Impurity 2h 0.67 1 0.2
Impurity 3 (if present)i 0.37 1 0.15
a  (4S)-4-Cyclohexyl-1-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.
b  (4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-d-proline propionate (ester).
c  Mixture of (4S)-4-cyclohexyl-1-[(S)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt and (4S)-4-cyclohexyl-1-[[(R)-[(R)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
d  (4R)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
e  (4S)-4-Phenyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
f  (4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-propoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester),sodium salt.
g  (2S,4S)-4-Cyclohexyl-1-pivaloylpyrrolidine-2-carboxylic acid.
h  2-((RS)-((SR)-2-Methyl-1-(propionyloxy)propoxy)(4-phenylbutyl)phosphinyl)acetic acid.
i  (S)-4-cyclohexyl-1-(3-oxopentanoyl)-l-proline.
•  Procedure 2
Sample solution:  Proceed as directed in the Assay.
Mobile phase:  Acetonitrile, phosphoric acid, and water (4000:2:15)
System suitability solution:  0.1 mg/mL of USP Fosinopril Sodium RS and 0.01 mg/mL each of USP Fosinopril Related Compound C RS and USP Fosinopril Related Compound D RS in the Mobile phase
Chromatographic system  
Mode:  LC
Detector:  UV 214 nm
Column:  4.6-mm × 25-cm; packing L12
Temperature:  45
Flow rate:  0.9 mL/min
Injection size:  20 µL
Run time:  Twice the retention time of fosinopril sodium
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 1.5 between fosinopril sodium and fosinopril related compound C
Analysis 
Sample:  Sample solution
Calculate the percentages of fosinopril related compound C and fosinopril related compound D only:
Result = (rU/rT) × 100
rU== peak response of fosinopril related compound C or fosinopril related compound D
rT== sum of all the peak responses
•  Procedure 3
Solution A:  1-in-500 solution of phosphoric acid
Mobile phase:  Acetonitrile and Solution A (14:11)
System suitability solution:  0.01 mg/mL each of USP Fosinopril Sodium RS, USP Fosinopril Related Compound E RS, and USP Fosinopril Related Compound F RS in Mobile phase
Sample solution:  0.2 mg/mL of Fosinopril Sodium in Mobile phase
Chromatographic system 
Mode:  LC
Detector:  UV 205 nm
Column:  4.6-mm × 25-cm; packing L11
Temperature:  45
Flow rate:  1 mL/min
Injection size:  20 µL
Run time:  Four times the retention time of fosinopril sodium
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 1.5 between fosinopril related compound F and fosinopril sodium; NLT 1.5 between fosinopril related compound E and fosinopril related compound F
Analysis 
Sample:  Sample solution
Measure the peak responses, carrying out the chromatography to four times the retention time of the fosinopril sodium peak.
Calculate the percentages of fosinopril related compound E and fosinopril related compound F only:
Result = (rU/rT) × 100
rU== peak response of fosinopril related compound E or fosinopril related compound F
rT== sum of all the peak responses
Acceptance criteria 
Individual impurities:  See Impurity Table 1. In addition to not exceeding the limits for impurities in Impurity Table 1, NMT 0.1% of any other individual impurity is found (calculated as directed in Procedure 1).
Total impurities:  NMT 1.5% for the total of Procedure 1, Procedure 2, and Procedure 3
SPECIFIC TESTS
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.
•  USP Reference Standards 11
USP Fosinopril Sodium RS Click to View Structure
USP Fosinopril Related Compound A RS Click to View Structure
(4S)-4-Cyclohexyl-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.
    C23H34NO5P         435.49
USP Fosinopril Related Compound B RS Click to View Structure
(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-d-proline propionate (ester), hemibarium salt, sesquihydrate.
    C30H45NO7P·½Ba·1½H2O         658.34
USP Fosinopril Related Compound C RS Click to View Structure
(4S)-4-Cyclohexyl-1-[(RS)-[(RS)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
    C30H45NNaO7P         585.64
USP Fosinopril Related Compound D RS Click to View Structure
(4R)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
    C30H45NNaO7P         585.64
USP Fosinopril Related Compound E RS Click to View Structure
(4S)-4-Phenyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
    C30H39NNaO7P         579.60
USP Fosinopril Related Compound F RS Click to View Structure
(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxypropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
    C29H43NNaO7P         571.62
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