Fosinopril Sodium
585.64l-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].» Fosinopril Sodium contains not less than 97.5 percent and not more than 102.0 percent of C30H45NNaO7P, calculated on the anhydrous basis.
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 .
USP Fosinopril Related Compound B RS .
USP Fosinopril Related Compound C RS .
USP Fosinopril Related Compound D RS .
USP Fosinopril Related Compound E RS .
USP Fosinopril Related Compound F RS .
11—
USP Fosinopril Sodium RS
.
USP Fosinopril Related Compound A RS
.
USP Fosinopril Related Compound B RS
.
USP Fosinopril Related Compound C RS
.
USP Fosinopril Related Compound D RS
.
USP Fosinopril Related Compound E RS
.
USP Fosinopril Related Compound F RS
.
Identification,
Infrared Absorption 197M.
197M.
Water, Method I 921:
not more than 0.2%.
921:
not more than 0.2%.
Heavy metals, Method II 231:
0.002%.
231:
0.002%.
Related compounds—
test 1—
Mobile phase and Chromatographic system—
Proceed as directed in the Assay.
System suitability solution—
Transfer about 10 mg of USP Fosinopril Sodium RS, and about 1 mg each of USP Fosinopril Related Compound A RS and USP Fosinopril Related Compound B RS to a 100-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume, and mix.
Test solution—
Use the Assay preparation.
Procedure—
Proceed as directed in the Assay, and measure the areas for each component in the chromatogram obtained, carrying out the chromatography to four times the retention time of the fosinopril sodium peak. Calculate the percentage of each individual related compound by the formula:
100(ri / rs)
in which ri is the response of any individual peak, other than the fosinopril sodium peak; and rs is the sum of the responses of all the peaks. [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 Table 1.]
Table 1
| Relative Retention Time |
Fosinopril Related Compound |
Test | Limit (%) |
| 2.0 | A1 | 1 | 0.3 |
| 0.7 | B2 | 1 | 1.0 |
| 1.2 | C3 | 2 | 0.3 |
| 1.3 | D4 | 2 | 0.3 |
| 0.8 | E5 | 3 | 0.3 |
| 0.9 | F6 | 3 | 0.3 |
| 0.12 | Impurity 17 | 1 | 0.3 |
| 0.24 | Impurity 28 | 1 | 0.2 |
|
1
(4S)-4-Cyclohexyl-1-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.
|
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|
2
(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-d-proline propionate (ester).
|
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|
3
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.
|
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|
4
(4R)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
|
|||
|
5
(4S)-4- Phenyl-1-[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester), sodium salt.
|
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|
6
(4S)-4-Cyclohexyl-1-[(R)-[(S)-1-hydroxy-propoxy](4-phenylbutyl)phosphinyl]acetyl-l-proline propionate (ester),sodium salt.
|
|||
|
7
(2S,4S)-4-Cyclohexyl-1-pivaloylpyrrolidine-2-carboxylic acid.
|
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|
8
2-((RS)-((SR)-2-Methyl-1-(propionyloxy)propoxy)(4-phenylbutyl)phosphinyl)acetic acid.
|
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test 2—
Mobile phase—
Prepare a degassed mixture of acetonitrile, water, and phosphoric acid (4000:15:2). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard solution—
Use the Standard preparation, prepared as directed in the Assay.
Resolution solution—
Transfer about 1 mg each of USP Fosinopril Sodium RS, USP Fosinopril Related Compound C RS, and USP Fosinopril Related Compound D RS to a 100-mL volumetric flask. Dissolve in and dilute with the Standard solution to volume, and mix.
Test solution—
Use the Assay preparation.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 214-nm detector and a 4.6-mm × 25-cm column that contains packing L12. The column temperature is maintained at 45
. The flow rate is about 0.9 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between fosinopril sodium and fosinopril related compound C is not less than 1.5.
621)—
The liquid chromatograph is equipped with a 214-nm detector and a 4.6-mm × 25-cm column that contains packing L12. The column temperature is maintained at 45. The flow rate is about 0.9 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between fosinopril sodium and fosinopril related compound C is not less than 1.5.
Procedure—
Inject about 20 µL of the Test solution into the chromatograph, record the chromatogram, and measure the peak areas, carrying out the chromatography to two times the retention time of the fosinopril sodium peak. Calculate the percentages of fosinopril related compound C and fosinopril related compound D only by the formula:
100(ri / rs)
in which ri is the peak response of fosinopril related compound C or fosinopril related compound D; and rs is the sum of the responses of all the peaks.
test 3—
0.2% Phosphoric acid solution—
Prepare a 1 in 500 solution of phosphoric acid.
Mobile phase—
Prepare a degassed mixture of acetonitrile and 0.2% Phosphoric acid solution (560:440). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Resolution solution—
Transfer about 1 mg each of USP Fosinopril Sodium RS, USP Fosinopril Related Compound E RS, and USP Fosinopril Related Compound F RS to a 100-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume, and mix.
Test solution—
Transfer about 10 mg of Fosinopril Sodium, accurately weighed, to a 50-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 205-nm detector and a 4.6-mm × 25-cm column that contains packing L11. The column temperature is maintained at 45. The flow rate is about 1 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between fosinopril related compound F and fosinopril sodium is not less than 1.5, and the resolution between fosinopril related compound E and fosinopril related compound F is not less than 1.5.
621)—
The liquid chromatograph is equipped with a 205-nm detector and a 4.6-mm × 25-cm column that contains packing L11. The column temperature is maintained at 45. The flow rate is about 1 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between fosinopril related compound F and fosinopril sodium is not less than 1.5, and the resolution between fosinopril related compound E and fosinopril related compound F is not less than 1.5.
Procedure—
Inject about 20 µL of the Test solution into the chromatograph, record the chromatogram, and measure the peak areas, 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, using the formula below:
100(ri / rs)
in which ri is the peak response of fosinopril related compound E or fosinopril related compound F; and rs is the sum of the responses of all the peaks. In addition to not exceeding the limits for impurities in Table 1, not more than 0.1% of any other individual impurity is found (calculated as directed for the Procedure in Test 1); and not more than 1.5% of total impurities is found.
Assay—
Mobile phase—
Prepare a degassed mixture of acetonitrile, water, and phosphoric acid (2000:10:1). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
System suitability solution—
Transfer about 10 mg of USP Fosinopril Sodium RS, and about 1 mg of USP Fosinopril Related Compound B RS to a 100-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume, and mix.
Standard preparation—
Dissolve an accurately weighed quantity of USP Fosinopril Sodium RS in Mobile phase to obtain a solution having a known concentration of about 0.10 mg per mL.
Assay preparation—
Transfer about 25 mg of Fosinopril Sodium, accurately weighed, to a 250-mL volumetric flask. Dissolve in and dilute with Mobile phase to volume, and mix.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 214-nm detector and a 3.9-mm × 15-cm column that contains packing L3. The column temperature is maintained at 33. The flow rate is about 1.2 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between fosinopril related compound B and fosinopril sodium is not less than 2.0; and the relative standard deviation of the fosinopril sodium peak response for replicate injections is not more than 2.0%.
621)—
The liquid chromatograph is equipped with a 214-nm detector and a 3.9-mm × 15-cm column that contains packing L3. The column temperature is maintained at 33. The flow rate is about 1.2 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between fosinopril related compound B and fosinopril sodium is not less than 2.0; and the relative standard deviation of the fosinopril sodium peak response for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the amount, in mg, of C30H45NNaO7P in the portion of Fosinopril Sodium taken by the formula:
250CS (rU / rS)
in which CS is the concentration, in mg per mL, of USP Fosinopril Sodium RS in the Standard preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
Chromatographic Column—
| Topic/Question | Contact | Expert Committee |
| Monograph | Sujatha Ramakrishna, Ph.D.
Scientist 1-301-816-8349 |
(MDCV05) Monograph Development-Cardiovascular |
| Reference Standards | Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org |
USP32–NF27 Page 2449
Pharmacopeial Forum: Volume No. 34(3) Page 613
Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.