Quinapril 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

Quinapril and Hydrochlorothiazide Tablets contain NLT 95.0% and NMT 105.0% of the labeled amounts of quinapril (C₂₅H₃₀N₂O₅) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂).

2 IDENTIFICATION

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

Assay.

Add the following:

B. The UV spectra of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay. (USP 1-May-2023)

3 ASSAY

Change to read:

3.1 Procedure

Solution A: Dissolve 1.36 g (USP 1-May-2023) of monobasic potassium phosphate in 1000 mL of (USP 1-May-2023) water, add 2 mL of triethylamine, and adjust with phosphoric acid to a pH of 3.0. Pass through a suitable filter of 0.45-µm pore size. (USP 1-May-2023)

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Solution A and Solution B (50:50)

Standard stock solution A: 0.45 mg/mL of USP Quinapril Hydrochloride RS in Diluent

Standard stock solution B: 0.5 mg/mL of USP Hydrochlorothiazide RS in Diluent

Standard solution: Known concentrations of USP Quinapril Hydrochloride RS and USP Hydrochlorothiazide RS in Diluent from (USP 1-May-2023)

Standard stock solution A and Standard stock solution B as given in Table 2. (USP 1-May-2023)

Table 2

(USP 1-May-2023)

Sample stock solution: Transfer 5 Tablets into a 250-mL volumetric flask, add 50 mL of Diluent, and sonicate for 15 min. Add about 50 mL of acetonitrile, and sonicate for 15 min with shaking. Add 50 mL of Diluent, and sonicate for 15 min. Dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size. (USP 1-May-2023)

Sample solution: Nominally (USP 1-May-2023) 0.02 mg/mL of quinapril in Diluent from the Sample stock solution.

[Note—The hydrochlorothiazide concentration may vary depending on the ratio of quinapril to hydrochlorothiazide in the Tablet. (USP 1-May-2023)]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm. For Identification B, use a diode array detector in the range of 190–400 nm. (USP 1-May-2023)

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for quinapril and hydrochlorothiazide

Relative standard deviation: NMT 2.0% for quinapril and hydrochlorothiazide

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quinapril (C₂₅H₃₀N₂O₅) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of quinapril from the Sample solution

r_S = peak response of quinapril from the Standard solution

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

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

M_r1 = molecular weight of quinapril, 438.52

M_r2 = molecular weight of quinapril hydrochloride, 474.98

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: 95.0%–105.0% for both quinapril and hydrochlorothiazide (USP 1-May-2023)

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Medium: Water; 900 mL

Apparatus 1: 100 rpm

Time: 20 min

Proceed as directed in the Assay.

Calculate the percentage of the labeled amount of quinapril (C₂₅H₃₀N₂O₅) dissolved:

Result = (r_U/r_S) × C_S/L × V × (M_r1/M_r2) × 100

r_U = peak response of quinapril from the Sample solution

r_S = peak response of quinapril from the Standard solution

C_S = concentration of USP Quinapril Hydrochloride RS in the Standard solution (mg/mL), (USP 1-May-2023)

L = label claim for quinapril (USP 1-May-2023) (mg/Tablet)

V = volume of Medium, 900 mL

M_r1 = molecular weight of quinapril, 438.52

M_r2 = molecular weight of quinapril hydrochloride, 474.98

Calculate the percentage of the labeled amount of hydrochlorothiazide (C₇H₈ClN₃O₄S₂) 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) (USP 1-May-2023)

L = label claim for hydrochlorothiazide (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amounts of quinapril (C₂₅H₃₀N₂O₅) and hydrochlorothiazide (C₇H₈ClN₃O₄S₂) is dissolved.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

Solution A, Solution B, (USP 1-May-2023) Diluent, and Sample stock solution: (USP 1-May-2023) Prepare as directed in the Assay.

Mobile phase: See Table 3.

Table 3

Sensitivity solution: 0.22 µg/mL of USP Quinapril Hydrochloride RS in Diluent (USP 1-May-2023)

Standard solution: 0.45 µg/mL each of USP Quinapril Hydrochloride RS, USP Quinapril Related Compound A RS, and USP Quinapril Related

Compound B RS, (USP 1-May-2023) and 0.5 µg/mL each of USP Hydrochlorothiazide RS and USP Benzothiadiazine Related Compound A

RS (USP 1-May-2023) in Diluent

(USP 1-May-2023)

Sample solution: For Tablet strengths of 10 mg/12.5 mg and 20 mg/12.5 mg of quinapril

(USP 1-May-2023) /hydrochlorothiazide, use the Sample stock solution as is. For a Tablet strength of 20 mg/25 mg of quinapril

(USP 1-May-2023) /hydrochlorothiazide, dilute 5 mL of the Sample stock solution with Diluent to 10 mL.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

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

Temperatures

Autosampler: 5°

Column: 35°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Samples: Sensitivity solution and (USP 1-May-2023) Standard solution

Suitability requirements

(USP 1-May-2023)

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

Relative standard deviation: NMT 5.0% for quinapril and hydrochlorothiazide, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution (USP 1-May-2023)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of quinapril related compound A and quinapril related compound B in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of quinapril related compound A or quinapril related compound B from the Sample solution

r_S = peak response of quinapril related compound A or quinapril related compound B (USP 1-May-2023) from the Standard solution

C_S = concentration of USP Quinapril Related Compound A RS or (USP 1-May-2023) USP Quinapril Related Compound B RS in the Standard solution (mg/mL)

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

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

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of benzothiadiazine related compound A from the Sample solution

r_S = peak response of benzothiadiazine related compound A from the Standard solution

C_S = concentration of USP Benzothiadiazine Related Compound A RS in the Standard solution (mg/mL)

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

Calculate the percentage of any unspecified (USP 1-May-2023) impurity in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of any unspecified (USP 1-May-2023) impurity from the Sample solution

r_S = peak response of quinapril from the Standard solution

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

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

M_r1 = molecular weight of quinapril, 438.52

M_r2 = molecular weight of quinapril hydrochloride, 474.98

Acceptance criteria: See Table 4. The reporting threshold is 0.1%. (USP 1-May-2023)

Table 4

ᵃ 6-Chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. (USP 1-May-2023)

ᵇ Process related impurity, monitored in the drug substance.

ᶜ 5,6-Dichloro-3,4-dihydro-2H-benzothiadiazine-7-sulfonamide 1,1-dioxide. (USP 1-May-2023)

ᵈ 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.

ᵉ (S)-2-{[(S)-1-Methoxy-1-oxo-4-phenylbutan-2-yl]-L-alanyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

ᶠ (S)-2-{[(S)-1-Isopropoxy-1-oxo-4-phenylbutan-2-yl]-L-alanyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

ᵍ (S)-2-{[(S)-4-Cyclohexyl-1-ethoxy-1-oxobutan-2-yl]-L-alanyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

ʰ Benzyl (S)-2-{[(S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]-L-alanyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate. (USP 1-May-2023)

ⁱ Total impurities does not include quinapril related compound B and benzothiadiazine related compound A.

5 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, and protect from light. Store at controlled room temperature.

Change to read:

USP Reference Standards 〈11〉

USP Benzothiadiazine Related Compound A RS

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

C₆H₈ClN₃O₄S₂ 285.73

USP Hydrochlorothiazide RS

USP Quinapril Hydrochloride RS

USP Quinapril Related Compound A RS

Ethyl[3S-[2(R*),3a,11aβ]]-1,3,4,6,11,11a-hexahydro-3-methyl-1,4-dioxo-α-(2-phenylethyl)-2H-pyrazino[1,2-b]isoquinoline-2-acetate;

Also known as Ethyl (S)-2-{(3S,11aS)-3-methyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinolin-2-yl}-4-phenylbutanoate.

(USP 1-May-2023)

C₂₅H₂₈N₂O₄ 420.51

USP Quinapril Related Compound B RS

3-Isoquinolinecarboxylic acid, 2-[2-[(1-carboxy-3-phenylpropyl)amino]-1-oxopropyl]-1,2,3,4-tetrahydro-, 3S-[2[R*(R*)],3R*]]-;

Also known as (S)-2-{[(S)-1-Carboxy-3-phenylpropyl]-L-alanyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. (USP 1-May-2023)

C₂₃H₂₆N₂O₅ 410.47