Fosinopril Sodium and Hydrochlorothiazide Tablets

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

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

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1 DEFINITION

Fosinopril Sodium and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of fosinopril sodium (C₃₀H₄₅NNaO₇P) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂).

2 IDENTIFICATION

Change to read:

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

Fosinopril Sodium: Transfer an amount equivalent to 25 mg of fosinopril sodium from finely powdered Tablets to a 100-mL beaker containing 40 mL of water. Heat at 30° for 5 min with stirring, and filter through a fritted disk of medium pore size. Centrifuge the filtrate at 2500 rpm for 30 min. 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 isobutyl 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 an amount equivalent to 37.5 mg of hydrochlorothiazide from finely powdered Tablets to a 250-mL beaker containing 120 mL of water, heat at 30° for 5 min with stirring, and filter through a a fritted disk of medium pore size. 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.

Acceptance criteria: Meet the requirements

B. The retention times of fosinopril and hydrochlorothiazide peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Buffer: 0.01 M monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 2.0.

Solution A: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent A: Acetonitrile and water (1:2)

Diluent B: Acetonitrile and 0.001 N hydrochloric acid (1:2)

System suitability solution: 0.08 mg/mL each of USP Hydrochlorothiazide RS and USP Fosinopril Sodium RS, and 0.025 mg/mL of USP Chlorothiazide RS in Diluent B

Standard stock solution A: 2.0 mg/mL of USP Fosinopril Sodium RS in Diluent A

Standard stock solution B: 2.0 mg/mL of USP Hydrochlorothiazide RS in Diluent B

Standard solution: 0.08 mg/mL each of USP Fosinopril Sodium RS and USP Hydrochlorothiazide RS from Standard stock solution A and Standard stock solution B, respectively, in Diluent B

Sample stock solution: Nominally equivalent to 0.1 mg/mL of fosinopril sodium and 0.125 mg/mL of hydrochlorothiazide in Diluent B from NLT 20 finely powdered Tablets. Initially add Diluent B to fill 75% of the final volume, and sonicate for about 10 min. Shake by mechanical means for 15 min, and dilute with Diluent B to volume. Pass a portion of this solution through a filter (PTFE or PVDF) of 0.45-μm pore size, and collect the rest of the filtrate.

Sample solution: 0.075 mg/mL of fosinopril sodium in Diluent B from Sample stock solution

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 206 nm

Column: 4.6-mm × 15-cm; packing L1

Flow rate: 1.0 mL/min

Injection volume: 20 μL

3.3 System suitability

Samples: System suitability solution and Standard solution

3.4 Suitability requirements

Resolution: NLT 1.8 between chlorothiazide and hydrochlorothiazide, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of fosinopril sodium (C₃₀H₄₅NNaO₇P) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of fosinopril from the Sample solution

r _S= peak response of fosinopril from the Standard solution

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

C_U = nominal concentration of fosinopril sodium in the Sample solution (mg/mL)

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of hydrochlorothiazide from the Sample solution

r_S = peak response of hydrochlorothiazide from the Standard solution

C_S = concentration of USP Hydrochlorothiazide RS in the Standard solution (mg/mL)

C_U = nominal concentration of hydrochlorothiazide in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% of the labeled amount of fosinopril sodium (C₃₀H₄₅NNaO₇P) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂)

4 PERFORMANCE TESTS

Dissolution 〈711〉

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Buffer: 0.01 M monobasic potassium phosphate; pH 3.0

Mobile phase: Methanol, acetonitrile, and Buffer (350:200:450) Standard stock solution A: 0.1 mg/mL of USP Fosinopril Sodium RS. Initially add 0.3 mL of methanol per mg of USP Fosinopril Sodium RS, and dilute with water to final concentration.

Standard stock solution B: 0.1 mg/mL of USP Hydrochlorothiazide RS. Initially add 0.3 mL of methanol per mg of USP Fosinopril Sodium RS, and dilute with water to final concentration.

Standard solution: Mix 25 mL of Standard stock solution B and x25 mL of Standard stock solution A, x being the ratio of the respective labeled amounts, in mg, of fosinopril sodium to that of hydrochlorothiazide per Tablet, and dilute with water to 200 mL.

System suitability solution: 0.05 mg/mL of USP Fosinopril Related Compound H RS and 0.002 mg/mL of USP Hydrochlorothiazide RS. Initially add 1 mL of methanol per mg of USP Fosinopril Related Compound H RS to dissolve, add Standard stock solution B, and dilute with water to final concentration.

Sample solution: Pass portions of the solution under test through an Acrylic filter of 1.2-μm pore size. Do not use glass filters.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detectors

UV 215 nm: For Standard solution and System suitability solution

UV 272 nm: For hydrochlorothiazide from 0 to 5 min

UV 210 nm: For fosinopril sodium from 5 to 9 min

Column: 4.6-mm × 25-cm; 5-μm packing L10

Column temperature: 40°

Flow rate: 1.3 mL/min

Injection volume: 50 μL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between fosinopril related compound H and hydrochlorothiazide, System suitability solution

Relative standard deviation: NMT 1.5%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of fosinopril sodium (C₃₀H₄₅NNaO₇P) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂) dissolved.

Tolerances: NLT 80% (Q) of the labeled amount of fosinopril sodium (C₃₀H₄₅NNaO₇P) and NLT 75% (Q) of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) are dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

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

Standard solution: 4 μg/mL each of USP Fosinopril Sodium RS and USP Hydrochlorothiazide RS in Diluent B

System suitability solution: 5 μg/mL each of USP Chlorothiazide RS, USP Fosinopril Related Compound A RS, and USP Benzothiadiazine Related Compound A RS; and 0.5 mg/mL each of USP Hydrochlorothiazide RS and USP Fosinopril Sodium RS in Diluent B

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.8 between chlorothiazide and hydrochlorothiazide, System suitability solution

Relative standard deviation: NMT 10.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Measure the peak responses eluting between 2.7 min and 27 min.

Calculate the percentage of any impurity or degradation product in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of fosinopril or hydrochlorothiazide from the Standard solution

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

C_U = nominal concentration of fosinopril sodium or hydrochlorothiazide in the Sample solution (mg/mL)

F = relative response factor of each impurity relative to fosinopril sodium or hydrochlorothiazide (see Table 2)

Acceptance criteria: See Table 2.

Table 2

^a 4-Amino-6-chloro-1,3-benzenedisulfonamide.

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

^c 6-Chloro-2(H)-1,2,4-benzothiazine-7-sulfonamide.

^d Relative to hydrochlorothiazide.

6 ADDITIONAL REQUIREMENTS

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

USP Reference Standards 〈11〉

USP Benzothiadiazine Related Compound A RS

4-Amino-6-chloro-1,3-benzenedisulfonamide.

C₆H₈ClN₃O₄S₂ 285.73

USP Chlorothiazide RS

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 H RS

4-Phenylbutyl phosphonic acid.

C₁₀H₁₅O₃P 214.20

USP Hydrochlorothiazide RS