Fosinopril Sodium and Hydrochlorothiazide Tablets
» Fosinopril Sodium and Hydrochlorothiazide Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of fosinopril sodium (C30H45NNaO7P) and of hydrochlorothiazide (C7H8ClN3O4S2).
Packaging and storage—
Preserve in tight containers, and store at controlled room temperature.
USP Reference standards 
11
—
11—
USP Benzothiadiazine Related Compound A RS 
4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
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4-Amino-6-chloro-1,3-benzenedisulfonamide.
C6H8ClN3O4S2 285.73
USP Chlorothiazide RS
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USP Fosinopril Sodium RS
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USP Fosinopril Related Compound A RS
(4S)-4-Cyclohexyl-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.
C23H34NO5P 435.49
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(4S)-4-Cyclohexyl-[(4-phenylbutyl)phosphinyl]acetyl-l-proline.
C23H34NO5P 435.49
USP Fosinopril Related Compound H RS
4-phenylbutyl phosphonic acid.
C10H15O3P 214.20
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4-phenylbutyl phosphonic acid.
C10H15O3P 214.20
USP Hydrochlorothiazide RS
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Identification—
A:
Infrared Absorption 197F—
197F—
fosinopril sodium—
Transfer a portion of the finely powdered Tablets, equivalent to about 25 mg of fosinopril sodium, to a 100-mL beaker containing 40 mL of water, heat at 30
for 5 minutes with stirring, and filter through a funnel having a medium-porosity fritted disk. Centrifuge the filtrate at 2500 rpm for 30 minutes. Adjust the filtrate with hydrochloric acid to a pH of 1 to precipitate the fosinopril, and filter through a fritted-disk funnel. Dissolve the precipitate by passing methyl iosobutyl ketone through the filter, and evaporate the filtrate to dryness under a stream of nitrogen. Proceed as directed, using the oily residue so obtained and a similarly prepared residue from 25 mg of USP Fosinopril Sodium RS.
for 5 minutes with stirring, and filter through a funnel having a medium-porosity fritted disk. Centrifuge the filtrate at 2500 rpm for 30 minutes. Adjust the filtrate with hydrochloric acid to a pH of 1 to precipitate the fosinopril, and filter through a fritted-disk funnel. Dissolve the precipitate by passing methyl iosobutyl ketone through the filter, and evaporate the filtrate to dryness under a stream of nitrogen. Proceed as directed, using the oily residue so obtained and a similarly prepared residue from 25 mg of USP Fosinopril Sodium RS.
hydrochlorothiazide—
Transfer a portion of the finely powdered Tablets, equivalent to about 37.5 mg of hydrochlorothiazide, to a 250-mL beaker containing 120 mL of water, heat at 30 for 5 minutes with stirring, and filter through a funnel having a medium-porosity fritted disk. Wash the precipitate with 60 mL of methylene chloride and glacial acetic acid (90:10) mixture, and discard the filtrate. Dissolve the precipitate by passing 10 mL of methyl isobutyl ketone through the filter, and evaporate the filtrate to dryness under a stream of nitrogen. Proceed as directed, using the waxy residue so obtained and a similarly prepared residue from 37 mg of USP Hydrochlorothiazide RS.
for 5 minutes with stirring, and filter through a funnel having a medium-porosity fritted disk. Wash the precipitate with 60 mL of methylene chloride and glacial acetic acid (90:10) mixture, and discard the filtrate. Dissolve the precipitate by passing 10 mL of methyl isobutyl ketone through the filter, and evaporate the filtrate to dryness under a stream of nitrogen. Proceed as directed, using the waxy residue so obtained and a similarly prepared residue from 37 mg of USP Hydrochlorothiazide RS.
B:
The retention times of the fosinopril sodium and hydrochlorothiazide peaks in the chromatogram of the Assay preparation correspond to those of the Standard preparation, as obtained in the Assay.
Dissolution 711—
711—
Medium:
water; 900 mL.
Apparatus 2:
50 rpm.
Time:
30 minutes.
Mobile phase—
Prepare a filtered and degassed mixture of 0.01 M monobasic potassium phosphate (pH 3.0), methanol, and acetonitrile (45:35:20). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard stock solutions—
Separately dissolve about 20 mg of USP Fosinopril Sodium RS and USP Hydrochlorothiazide RS accurately weighed in 6 mL of methanol, and dilute with water to obtain solutions (Standard stock solution A and B) having known concentrations of about 0.1 mg per mL of USP Fosinopril Sodium RS and USP Hydrochlorothiazide RS, respectively.
Standard solution—
Mix 25 mL of Standard stock solution B and x25 mL of Standard stock solution A, and dilute with water to 200 mL, x being the ratio of the respective labeled amounts, in mg, of fosinopril sodium to that of hydrochlorothiazide per Tablet.
Resolution solution—
Transfer 5 mg of USP Fosinopril Related Compound H RS into a 100-mL volumetric flask, and dissolve in 5 mL of methanol. Add 2.0 mL of Standard stock solution B, dilute with water to volume, and mix.
Test solution—
Use portions of the solution under test passed through a 1.2-µm acrylic filter. [note—Do not use glass filters. ]
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a variable wavelength detector set at 210 nm and 272 nm and a 4.6-mm × 25-cm column, maintained at 40 that contains 5-µm packing L10. The flow rate is about 1.3 mL per minute. With the detector set at 215 nm, chromatograph the Resolution solution and the Standard solution, and record the peak responses as directed for Procedure: the resolution, R, between the fosinopril related compound H peak and the hydrochlorothiazide peak is not less than 1.5; and the relative standard deviation for replicate injections of the Standard solution is not more than 1.5%.
621)—
The liquid chromatograph is equipped with a variable wavelength detector set at 210 nm and 272 nm and a 4.6-mm × 25-cm column, maintained at 40 that contains 5-µm packing L10. The flow rate is about 1.3 mL per minute. With the detector set at 215 nm, chromatograph the Resolution solution and the Standard solution, and record the peak responses as directed for Procedure: the resolution, R, between the fosinopril related compound H peak and the hydrochlorothiazide peak is not less than 1.5; and the relative standard deviation for replicate injections of the Standard solution is not more than 1.5%.
Procedure—
Separately inject equal volumes (about 50 µL) of the Test solution and the Standard solution, and record the chromatograms with the detector set at 272 nm from 0 to 5 minutes and at 210 from 5 to 9 minutes, for hydrochlorothiazide and fosinopril sodium, respectively. Measure the responses for the major peaks, and calculate the amount of C30H45NNaO7P and of C7H8ClN3O4S2 dissolved.
Tolerances—
Not less than 80% (Q) of the labeled amount of C30H45NNaO7P and not less than 75% (Q) of the labeled amount of C7H8ClN3O4S2 are dissolved in 30 minutes.
Uniformity of dosage units:
meet the requirements.
Related compounds—
Solution A, Solution B, Diluent 2, and Mobile phase—
Proceed as directed in the Assay.
Standard solution—
Dissolve accurately weighed quantities of USP Fosinoprol Sodium RS and USP Hydrochlorothiazide RS in a suitable volumetric flask in Diluent 2 to obtain a solution having a known concentration of about 0.004 mg per mL of each USP Reference Standard.
System suitability solution—
Dissolve accurately weighed quantities of USP Chlorothiazide RS, USP Hydrochlorothiazide RS, USP Fosinopril Sodium RS, USP Fosinopril Related Compound A RS, and USP Benzothiadiazine Related Compound A RS in a suitable volumetric flask in Diluent 2. Dilute stepwise, if necessary, to obtain a solution having a known concentration of about 0.005 mg per mL of USP Chlorothiazide RS, USP Fosinopril Related Compound A RS, and USP Benzothiadiazine Related Compound A RS and about 0.5 mg per mL of USP Hydrochlorothiazide RS and of USP Fosinopril Sodium RS.
Test solution—
Use the Assay preparation.
Chromatographic system—
Proceed as directed in the Assay. Chromatograph the Standard solution and the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between chlorothiazide and hydrochlorothiazide is not less than 1.8; and the relative standard deviation for replicate injections is not more than 10.0%.
Procedure—
Separately inject equal volumes (about 20 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses eluting between 2.7 minutes and 27 minutes. Calculate the percentage of any impurity or degradation product in the portion of Tablets taken by the formula:
100(rU / rS)(CS / CS)(1/F)
in which rU is the individual peak response for each impurity obtained from the Test solution; rS is the response of the fosinopril sodium or hydrochlorothiazide in the Standard solution; F is the relative response factor of each impurity relative to fosinopril sodium or hydrochlorothiazide as mentioned in Table 1; and CS and CU are the concentrations, in mg per mL, of fosinopril sodium or hydrochlorothiazide in the Standard solution and the Test solution, respectively. The limits of impurities are specified in Table 1.
Table 1
| Component | Relative Retention Time (RRT) |
Relative Response Factor (RRF) |
Limit (%) |
|---|---|---|---|
| Benzothiadiazine related compound A1 | 0.81 (relative to hydrochlorothiazide) | 1.0 | NMT 0.5 |
| Fosinopril related compound A2 | 0.72 (relative to fosinopril) | 1.2 | NMT 4 |
| Chlorothiazide3 | 0.90 (relative to hydrochlorothiazide) | 1.7 | NMT 0.3 |
| Any other individual impurity | — | — | NMT 0.2 (relative to hydrochlorothiazide) |
| Total of all impurities | — | — | NMT 5.0 |
|
1
4-Amino-6-chloro-1,3-benzenedisulfonamide.
|
|||
|
2
(4S)-4-Cyclohexyl-1-[-(4-phenylbutyl)phosphinyl]acetyl-l-proline.
|
|||
|
3
6-Chloro-2(H)-1,2,4-benzothiazine-7-sulfonamide.
|
|||
Assay—
Solution A—
Prepare a filtered and degassed solution of 0.01 M monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 2.0.
Solution B—
Use acetonitrile.
Mobile phase—
Use variable mixtures of Solution A and Solution B as directed for Chromatographc system. Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Diluent 1—
Use a mixture of water and acetonitrile (2:1).
Diluent 2—
Use a mixture of 0.001 N hydrochloric acid and acetonitrile (2:1).
Standard preparation—
Transfer into two separate suitable volumetric flasks accurately weighed quantities of USP Fosinopril Sodium RS and USP Hydrochlorothiazide RS. Dissolve USP Fosinopril Sodium RS in Diluent 1 and USP Hydrochlorothiazide RS in Diluent 2 respectively, to obtain stock solutions having known concentrations of about 2.0 mg per mL. Dilute quantitatively, and stepwise if necessary, portions of these two solutions with Diluent 2 to obtain a solution having a known concentration of 0.08 mg per mL of USP Fosinopril Sodium RS and of USP Hydrochlorothiazide RS.
System suitability solution—
Dissolve accurately weighed quantities of USP Chlorothiazide RS, USP Hydrochlorothiazide RS, and USP Fosinopril Sodium RS in a suitable volumetric flask in Diluent 2 to obtain a solution having a known concentration of about 0.08 mg per mL of USP Hydrochlorothiazide RS and of USP Fosinopril Sodium RS and 0.025 mg per mL of the USP Chlorothiazide RS.
Assay preparation—
Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 10 mg of fosinopril and 12.5 mg of hydrochlorothiazide, to a 100-mL volumetric flask, add about 75 mL of Diluent 2, and sonicate for about 10 minutes. Shake by mechanical means for 15 minutes. Dilute with Diluent 2 to volume, and mix. Pass a portion of this solution through a filter (PTFE or PVDF) having a 0.45-µm or finer porosity, and collect the rest of the filtrate. Dilute further, stepwise if necessary, to obtain a solution having a known concentration of about 0.075 mg of fosinopril sodium.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 206-nm detector and a 4.6-mm × 15-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. The chromatograph is programmed as follows.
Chromatograph the Standard preparation and the System suitability solution (about 20 µL), and record the peak responses as directed for Procedure: the resolution, R, between the chlorothiazide and hydrochlorothiazide peaks is not less than 1.8; the tailing factor is less than 2.0; and the relative standard deviation for replicate injections is not more than 2.0%.
621)—
The liquid chromatograph is equipped with a 206-nm detector and a 4.6-mm × 15-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. The chromatograph is programmed as follows.
| Time (minutes) |
Solution A (%) | Solution B
(%) |
Elution |
|---|---|---|---|
| 0–2 | 88 | 12 | isocratic |
| 2–20 | 88®10 | 12®90 | linear gradient |
| 20–28 | 10 | 90 | isocratic |
| 28–37 | 10®88 | 90®12 | linear gradient |
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 peak responses. Calculate the percentage of fosinopril sodium (C30H45NNaO7P) in the portion of the Tablets taken by the formula:
100(rU / rS)(CS / CU)
in which r U and rS are the peak responses of fosinopril sodium in the Assay preparation and the Standard preparation, respectively; and C S and CU are the concentrations, in mg per mL, of fosinopril sodium in the Standard preparation and the Assay preparation, respectively. Calculate the percentage of hydrochlorothiazide (C7H8ClN3O4S2) in the portion of the Tablets taken by the formula:
100(rU / rS)(CS / CU)
in which rU and rS are the peak responses of hydrochlorothiazide in the Assay preparation and the Standard preparation, respectively; and C S and CU are the concentrations, in mg per mL, of hydrochlorothiazide in the Standard preparation and the Assay preparation, respectively.
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 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
|
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
USP35–NF30 Page 3284
Pharmacopeial Forum: Volume No. 33(1) Page 66