Fosinopril Sodium

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₃₀H₄₅NNaO₇P 585.64

l-Proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-, sodium salt, [1[S*(R*)],2α,4β]-;

(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt CAS RN®:

88889-14-9; UNII: NW2RTH6T2N.

1 DEFINITION

Fosinopril Sodium contains NLT 97.5% and NMT 102.0% of fosinopril sodium (C₃₀H₄₅NNaO₇P), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197M (CN 1-May-2020)

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

3.1 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

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 214 nm

Column: 3.9-mm × 15-cm; 5-μm packing L3

Column temperature: 33°

Flow rate: 1.2 mL/min

Injection volume: 20 μL

Run time: NLT 4 times the retention time of the fosinopril peak

3.3 System suitability

Sample: System suitability solution

3.4 Suitability requirements

Resolution: NLT 2.0 between fosinopril related compound B and fosinopril

Relative standard deviation: NMT 0.73% for the fosinopril peak

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of fosinopril sodium (C₃₀H₄₅NNaO₇P) in the portion of Fosinopril Sodium taken:

Result = (r_U/r_U) × (C_S/C_U) × 100

r_U = peak response of fosinopril from the Sample solution

r_U = peak response of fosinopril from the Standard solution

C_U = concentration of USP Fosinopril Sodium RS in the Standard solution (mg/mL)

C_U = concentration of Fosinopril Sodium in the Sample solution (mg/mL)

Acceptance criteria: 97.5%–102.0% on the anhydrous basis

4 IMPURITIES

4.1 Organic Impurities, Procedure 1

Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

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 in the portion of Fosinopril Sodium taken:

Result = (r_U/r_T) × 100

r_U = individual peak response, other than the fosinopril peak

r_T = sum of all the peak responses

Acceptance criteria: See Table 1.

Table 1

^a (S)-4-Cyclohexyl-1-(3-oxopentanoyl)-l-proline.

^b (2S,4S)-4-Cyclohexyl-1-pivaloylpyrrolidine-2-carboxylic acid.

^c 2-((RS)-((SR)-2-Methyl-1-(propionyloxy)propoxy)(4-phenylbutyl)phosphinyl)acetic acid.

^d (4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-d-proline propionate (ester). 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.

^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-hydroxypropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.

^g 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.

^h (4R)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.

ⁱ (4S)-4-Cyclohexyl-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.

^j Sum of all impurities from Organic Impurities, Procedure 1; Organic Impurities, Procedure 2; and Organic Impurities, Procedure 3.

4.2 Organic Impurities, Procedure 2

Mobile phase: Acetonitrile, phosphoric acid, and water (2000:1:7.5)

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 Mobile phase

Sample solution: Prepare as directed in the Assay.

4.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 214 nm

Column: 4.6-mm × 25-cm; 5-μm packing L14

Column temperature: 45°

Flow rate: 0.9 mL/min

Injection volume: 20 μL

Run time: NLT 2 times the retention time of the fosinopril peak

4.2.2 System suitability

Sample: System suitability solution

4.2.3 Suitability requirements

Resolution: NLT 1.5 between fosinopril and fosinopril related compound C

4.2.4 Analysis

Sample: Sample solution

Calculate the percentages of fosinopril related compound C and fosinopril related compound D only in the portion of Fosinopril Sodium

taken:

Result = (r_U/r_T) × 100

r_U = peak response of fosinopril related compound C or fosinopril related compound D

r_T = sum of all the peak responses

Acceptance criteria: See Table 1.

4.3 Organic Impurities, Procedure 3

Solution A: Phosphoric acid (1 in 500)

Mobile phase: Acetonitrile and Solution A (56:44)

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

4.3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 205 nm

Column: 4.6-mm × 25-cm; 5-μm packing L11

Column temperature: 45°

Flow rate: 1 mL/min

Injection volume: 20 μL

Run time: NLT 4 times the retention time of the fosinopril peak

4.3.2 System suitability

Sample: System suitability solution

4.3.3 Suitability requirements

Resolution: NLT 1.5 between fosinopril related compound F and fosinopril; NLT 1.5 between fosinopril related compound E and fosinopril related compound F

4.3.4 Analysis

Sample: Sample solution

Calculate the percentages of fosinopril related compound E and fosinopril related compound F in the portion of Fosinopril Sodium taken:

Result = (r_U/r_T) × 100

r_U = peak response of fosinopril related compound E or fosinopril related compound F

r_T = sum of all the peak responses

Acceptance criteria: See Table 1.

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I: NMT 0.2%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

USP Reference Standards 〈11〉

USP Fosinopril Sodium RS

USP Fosinopril Related Compound A RS

(4S)-4-Cyclohexyl-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.

C₂₃H₃₄NO₅P 435.49

USP Fosinopril Related Compound B RS

(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-d-proline propionate (ester), hemibarium salt, sesquihydrate.

C₃₀H₄₅NO₇P · 1⁄2Ba · 11⁄2H O 658.34

USP Fosinopril Related Compound C RS

(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

(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

(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

(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxypropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.

C₂₉H₄₃NNaO₇P 571.62