Benazepril Hydrochloride 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

Benazepril Hydrochloride and Hydrochlorothiazide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of benazepril hydrochloride (C₂₄H₂₈N₂O₅.HCI) and hydrochlorothiazide (C₇H₈CIN₃O₄S₂).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The UV spectra of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Buffer: Dissolve 3.45 g of sodium phosphate, monobasic in 1000 mL of water. Add 2.0 mL of triethylamine. Adjust with phosphoric acid to a pH of 6.8.

Mobile phase: Acetonitrile and Buffer (32:68)

Diluent: Acetonitrile and water (50:50)

Standard solution: Concentrations of USP Benazepril Hydrochloride RS and USP Hydrochlorothiazide RS in Diluent, prepared as directed in Table 1. Sonicate to dissolve if needed.

Table 1

Sample stock solution: Transfer a quantity of Tablets (NLT 10) to a 200-mL volumetric flask. Add 10% of the flask volume of water and shake mechanically until the Tablets are disintegrated and well dispersed. Add another 10% of the flask volume of acetonitrile, sonicate for 20 min, then mechanically shake for an additional 20 min. Dilute with Diluent to volume.

Sample solution: Dilute the Sample stock solution with Diluent to obtain nominal concentrations of benazepril hydrochloride and hydrochlorothiazide as directed in Table 1. Pass a portion through a suitable filter and discard the first few milliliters of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification B, use a diode array detector in the range of 210-400 nm.

Column: 4.6-mm × 15-cm; 5-µm packing LZ

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of benazepril

System suitability

Sample: Standard solution

[NOTE-The relative retention times for hydrochlorothiazide and benazepril are about 0.4 and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for benazepril and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for benazepril and hydrochlorothiazide

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of benazepril hydrochloride (C₂₄H₂₈N₂O₅.HCI) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of benazepril from the Sample solution

r_S = peak response of benazepril from the Standard solution

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

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

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈CIN₃O₄S₂) 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%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

Test 1

Medium: 0.1 N hydrochloric acid; 500 mL

Apparatus 1: 100 rpm

Time: 30 min

Buffer and Mobile phase: Prepare as directed in the Assay.

Standard stock solution A: 0.1 mg/mL of USP Benazepril Hydrochloride RS in Medium. Sonicate to dissolve if needed.

Standard stock solution B: 0.125 mg/mL of USP Hydrochlorothiazide RS in Medium. Sonicate to dissolve if needed.

Standard solution: USP Benazepril Hydrochloride RS and USP Hydrochlorothiazide RS in Medium, prepared as directed in Table 2 from Standard stock solution A and Standard stock solution B

Table 2

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of

the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 234 nm

Column: 4.6-mm x 15-cm; 5-µm packing LZ

Flow rate: 0.9 mL/min

Injection volume

For Tablet strength of 5/6.25 mg: 100 µL

For Tablet strengths of 10/12.5, 20/12.5, and 20/25 mg: 25 µL

Run time: NLT 2 times the retention time of benazepril

System suitability

Sample: Standard solution

[NOTE-The relative retention times for hydrochlorothiazide and benazepril are about 0.5 and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for benazepril and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for benazepril and hydrochlorothiazide

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of benazepril hydrochloride (C₂₄H₂₈N₂O₅.HCI) dissolved:

Result = (r_U/r_S) × (C_S/L) × V × 100

r_U = peak response of benazepril from the Sample solution

r_S = peak response of benazepril from the Standard solution

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

L = label claim (mg/Tablet)

V = volume of Medium, 500 mL

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈CIN₃O₄S₂) dissolved:

Result = (r_U/r_S) × (C_S/L) × V × 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)

L = label claim (mg/Tablet)

V = volume of Medium, 500 mL

Tolerances: NLT 80% (Q) of the labeled amount of benazepril hydrochloride (C24H28N2O5 HCI) and hydrochlorothiazide (C₂H₂CINOS₂) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 0.1 N hydrochloric acid: 500 mL

Apparatus 1: 100 rpm

Time: 30 min

Buffer: 3.75 g/L of potassium phosphate, dibasic in water. Adjust with phosphoric acid to a pH of 2.1.

Mobile Phase: Acetonitrile and Buffer (35:65)

Standard stock solution: 0.25 mg/mL of USP Hydrochlorothiazide RS, prepared as follows. Transfer a suitable amount of USP Hydrochlorothiazide RS to a volumetric flask. Add a volume of acetonitrile equivalent to 5% of the total flask volume and, if necessary, sonicate to dissolve. Dilute with Medium to volume.

Standard solution: (L2/500) mg/mL of USP Hydrochlorothiazide RS from Standard stock solution and (L,/500) mg/mL of USP Benazepril Hydrochloride RS diluted in Medium, where L, is the label claim for benazepril hydrochloride in mg/Tablet and L₂ is the label claim for hydrochlorothiazide in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of the filtrate. [NOTE-It is recommended to avoid using stainless steel cannula when sampling.]

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm for benazepril and UV 275 nm for hydrochlorothiazide

Column: 4.6-mm × 25-cm; 5-µm packing 11

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 1.5 times the retention time of benazepril

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for benazepril at 240 nm and hydrochlorothiazide at 275 nm

Relative standard deviation: NMT 2.0% for benazepril at 240 nm and hydrochlorothiazide at 275 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of benazepril hydrochloride (C₂₄H₂₈N₂O₅.HCI) dissolved:

Result = (r_U/r_S) × (C_S/L₁) x V x 100

r_U = peak response of benazepril from the Sample solution

r_S = peak response of benazepril from the Standard solution 

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

L₁ = label claim of benazepril hydrochloride (mg/Tablet)

V = volume of Medium, 500 mL

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈CIN₃O₄S₂) dissolved:

Result = (r_U/r_S) x (C_S/L₂) x V x 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)

L₂ = label claim of hydrochlorothiazide (mg/Tablet)

V = volume of Medium, 500 mL

Tolerances: NLT 80% (Q) of the labeled amount of benazepril hydrochloride (C24H28N2O5 HCI) and NLT 75% (Q) of the labeled amount of hydrochlorothiazide (C₂H₂CINOS₂) is dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

5.1 ORGANIC IMPURITIES

Solution A: Dissolve 3.45 g of sodium phosphate, monobasic in 1000 mL of water. Add 1.0 mL of triethylamine. Adjust with 5 N sodium hydroxide to a pH of 6.7.

Solution B: Acetonitrile and methanol (80:20)

Mobile phase: See Table 3.

Table 3

Diluent A: Acetonitrile and water (32:68)

Diluent B: Acetonitrile and water (50:50)

Diluent C: Acetonitrile and water (13:87)

System suitability stock solution A: 0.1 mg/mL each of USP Benazepril Related Compound B RS and USP Chlorothiazide RS, and 0.125 mg/mL of USP Benzothiadiazine Related Compound A RS in Diluent A. Sonicate to dissolve if needed.

System suitability stock solution B: 0.15 mg/mL of USP Benazepril Related Compound C RS prepared as follows. Transfer 3.75 mg of USP Benazepril Related Compound C RS into a 25-mL volumetric flask. Add 20 mL of Diluent B, sonicate, and dilute with water to volume.

System suitability solution: 10 µg/mL each of USP Benazepril Related Compound B RS and USP Chlorothiazide RS, 12.5 µg/mL of USP Benzothiadiazine Related Compound A RS, and 30 µg/mL of USP Benazepril Related Compound C RS from System suitability stock solution A and System suitability stock solution B, diluted with water

Standard stock solution 1: 0.1 mg/mL of USP Benazepril Hydrochloride RS and 0.125 mg/mL of USP Hydrochlorothiazide RS in Diluent A for Tablet strengths containing 5/6.25, 10/12.5, and 20/25 mg of benazepril hydrochloride and hydrochlorothiazide. Sonicate to dissolve if needed.

Standard stock solution 2: 0.1 mg/mL of USP Benazepril Hydrochloride RS and 0.0625 mg/mL of USP Hydrochlorothiazide RS in Diluent A for Tablet strength containing 20/12.5 mg of benazepril hydrochloride and hydrochlorothiazide. Sonicate to dissolve if needed.

Standard stock solution 3: 10 µg/mL of USP Benazepril Hydrochloride RS and 12.5 µg/mL of USP Hydrochlorothiazide RS for 5/6.25, 10/12.5, and 20/25 Tablet strengths prepared as follows. Transfer a suitable volume of Standard stock solution 1 to an appropriate volumetric flask. Add 30% of the flask volume of Diluent A. Dilute with water to volume.

Standard stock solution 4: 10 µg/mL of USP Benazepril Hydrochloride RS and 6.25 µg/mL of USP Hydrochlorothiazide RS for 20/12.5 Tablet strength prepared as follows. Transfer a suitable volume of Standard stock solution 2 into an appropriate volumetric flask. Add 30% of the flask volume of Diluent A. Dilute with water to volume.

Standard solution: USP Benazepril Hydrochloride RS and USP Hydrochlorothiazide RS prepared as directed in Table 4 from Standard stock solution 3 or Standard stock solution 4, diluted with Diluent C

Table 4

Sensitivity solution: 0.5 µg/mL of USP Benazepril Hydrochloride RS and 0.625 µg/mL of USP Hydrochlorothiazide RS from Standard solution, diluted with Diluent C

Sample solution: Finely powder a quantity of Tablets (NLT 20) and transfer a portion of the powder, equivalent to 50 mg of benazepril hydrochloride, to a 50-mL volumetric flask. Add 40% of the flask volume of Diluent A and sonicate for 20 min with frequent shaking. Dilute with water to volume to obtain the nominal concentrations of benazepril hydrochloride and hydrochlorothiazide as given in Table 5.

Table 5

Chromatographic system (See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Temperatures

Autosampler: 5°

Column: 30°

Flow rate: 1.2 mL/min

Injection volume: 50 µL

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[NOTE-See Table 6 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between benzothiadiazine related compound A and chlorothiazide, System suitability solution

Tailing factor: NMT 2.0 for benazepril and hydrochlorothiazide, Standard solution

Relative standard deviation: NMT 5% for benazepril and hydrochlorothiazide, Standard solution

Signal-to-noise ratio: NLT 10 for benazepril and hydrochlorothiazide, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of benazepril related compound B, benazepril related compound C, or any unspecified 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 benazepril related compound B, benazepril related compound C, or any unspecified degradation product from the Sample solution

r_S = peak response of benazepril from the Standard solution

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

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

F = relative response factor (see Table 6)

Calculate the percentage of benzothiadiazine related compound A in the portion of Tablets taken:

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

r_U = peak response of benzothiadiazine related compound A 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)

F = relative response factor (see Table 6)

Acceptance criteria: See Table 6.

Table 6

^a Process impurity included in the table for identification only. Process impurities are not to be reported or included in the total degradation products for the drug product.

^b 6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-1,2,4-benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

^c Ethyl (S)-2-{[(S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]amino)-4-phenylbutanoate.

^d Excluding benzothiadiazine related compound A and benazepril related compound C.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Protect from moisture and light. Store at controlled room temperature.

LABELING: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.

Change to read:

USP REFERENCE STANDARDS (11)

USP Benazepril Hydrochloride RS

USP Benazepril Related Compound B RS

2-[(S)-3-{[(R)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl]acetic acid hydrochloride; Also known as (ERR 1-Jul-2021) (3S) 3-[[(1R)-1-(Ethoxycarbonyl)-3-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid, monohydrochloride.

C₂₄H₂₈N₂O₅.HCI  460.95

USP Benazepril Related Compound C RS

(3S)-3-[[(1S)-1-Carboxy-3-phenylpropyl] amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benazepine]-1-acetic acid;

Also known as (S)-2-{[(S)-1-(Carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]amino)-4-phenylbutanoic acid.

C₂₂H₂₄N₂O₅  396.44

USP Benzothiadiazine Related Compound A RS

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

C₆H₈CIN₃O₄S₂  285.73

USP Chlorothiazide RS

USP Hydrochlorothiazide RS