Quinapril Hydrochloride

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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Change to read:

C₂₅H₃₀N₂O₅ · HCl 474.98

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

(S)-2-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1-ethyl ester, monohydrochloride;

(S)-2-{[(S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl]-L-alanyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride. (USP 1-May-2021)

CAS RN^®: 82586-55-8; UNII: 33067B3N2M.

Quinapril hydrochloride (acetone solvate):

C₂₅H₃₀N₂O₅ · HCl · C₃H₆O 533.06

CAS RN^®: 757964-89-9. (USP 1-May-2021)

1 DEFINITION

Change to read:

Quinapril Hydrochloride contains NLT 98.5% and NMT 101.5% of quinapril hydrochloride (C₂₅H₃₀N₂O₅ · HCl), calculated on the anhydrous basis.

If labeled as acetone solvate, it contains NLT 98.5% and NMT 101.5% of quinapril hydrochloride (C₂₅H₃₀N₂O₅ · HCl) calculated on the anhydrous and acetone-free basis. (USP 1-May-2021)

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K or 197A (USP 1-May-2021)

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

Change to read:

3.1 Procedure

Mobile phase: Acetonitrile, methanesulfonic acid, and water (28: 0.1: 72)

Diluent: Acetonitrile and pH 6.5 0.025 M monobasic ammonium phosphate solution (40:60)

System suitability solution: 2 mg/mL of USP Quinapril Hydrochloride RS and 0.005 mg/mL each of USP Quinapril Related Compound A RS and USP Quinapril Related Compound B RS in Diluent

Standard solution: 2 mg/mL of USP Quinapril Hydrochloride RS in Diluent

Sample solution: 2 mg/mL of Quinapril Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 214 nm

Columns

Guard: 4.6-mm × 3-cm; 5-µm packing L10

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

Flow rate: 1.5 mL/min

Injection volume: 10 µL

Run time: NLT 3 times retention time of quinapril (USP 1-May-2021)

System suitability

Samples: System suitability solution and Standard solution (USP 1-May-2021)

Suitability requirements

Resolution:

NLT 1.75 between quinapril and quinapril related compound A;

NLT 3.5 between quinapril and quinapril related compound B, System suitability solution

Tailing factor: NMT 2.0, Standard solution (USP 1-May-2021)

Relative standard deviation: NMT 0.55%, Standard solution (USP 1-May-2021)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of quinapril hydrochloride (C₂₅H₃₀N₂O₅ · HCl) in the portion of Quinapril Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 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 = concentration of Quinapril Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.5%–101.5% on the anhydrous basis and 98.5%–101.5% on the anhydrous and acetone-free basis if labeled as acetone solvate (USP 1-May-2021)

4 OTHER COMPONENTS

4.1 Content of Chloride

Sample: 100 mg of Quinapril Hydrochloride

Titrimetric system

(See Titrimetry 〈541〉.)

Mode: Direct titration

Titrant: 0.01 N silver nitrate VS

Analysis: Transfer the Sample to a 100-mL beaker. Dissolve in 50 mL of water and 10 mL of alcohol, and acidify with nitric acid. Titrate with Titrant using suitable electrodes. Perform a blank determination, and make any necessary corrections. Each milliliter of 0.01 N silver nitrate is equivalent to 0.3545 mg of chloride.

Acceptance criteria: 7.2%–7.6%

5 IMPURITIES

5.1 Residue on Ignition 〈281〉: NMT 0.1%

Delete the following:

5.2 Limit of Residual Solvents

Standard stock solution: Transfer 50 mL of dimethylformamide to a 200-mL volumetric flask. Add 75 mg each of acetone and acetonitrile and 30 mg each of methylene chloride and toluene, each weighed by difference. Dilute with dimethylformamide to volume.

Standard solution: 4.0 mL of the Standard stock solution, diluted with dimethylformamide to 50 mL

System suitability solution 1: Transfer 25 mL of dimethylformamide to a 50-mL volumetric flask. Add 35 µL of dehydrated alcohol and 25 µL of methylene chloride. Dilute with dimethylformamide to volume. Transfer 1.0 mL of this solution to a 50-mL volumetric flask, and dilute with dimethylformamide to volume.

System suitability solution 2: 2.0 mL of the Standard stock solution, diluted with dimethylformamide to 50 mL

Sample solution: 60 mg of Quinapril Hydrochloride to a suitable headspace vial, add 5.0 mL of dimethylformamide, seal, and shake to dissolve.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.53 - mm * 30 - m fused silica column coated with a 1.0-µm film of phase G16 and a split injection system

Carrier gas: Helium

Flow rate: 6 mL/min

Sampler: Headspace

Vial pressure: 6.1 psi

Split flow rate: 100 mL/min (back pressure of 3.5 psi)

Injection volume: 1 mL

Temperature

Injector port: 180°

Detector: 240°

Oven temperature of the headspace sampler: 60°

Headspace loop and transfer lines: 65°

[NOTE-The vials are equilibrated for 10 min prior to injection, and injection occurs every 36 min.]

Column temperature: See the temperature table below.

System suitability

Samples: System suitability solution 1 and System suitability solution 2

[NOTE-The relative retention times for methylene chloride and alcohol are about 0.94 and 1.0, respectively, System suitability solution 1.]

Suitability requirements

Resolution: NLT 1.2 between methylene chloride and alcohol, System suitability solution 1

Column efficiency: NLT 4900 theoretical plates, from the methylene chloride peak of System suitability solution 1

Tailing factor: NMT 1.7 for the methylene chloride peak, System suitability solution 1

Relative standard deviation: NMT 15.0%, System suitability solution 2

Analysis

Samples: Standard solution and Sample solution

Separately calculate the percentages, by weight, of acetone, acetonitrile, methylene chloride, and toluene in the portion of Quinapril Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of the relevant solvent of the Sample solution

r_S = peak response of the relevant solvent of the Standard solution

C_S = concentration of the relevant solvent in the Standard solution (mg/mL)

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

Acceptance criteria

Acetone: NMT 0.25%

Acetonitrile: NMT 0.25%

Methylene chloride: NMT 0.1%

Toluene: NMT 0.1% (USP 1-May-2021)

Change to read:

5.3 Organic Impurities

Mobile phase, Diluent, System suitability solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Sensitivity solution: 2 µg/mL of USP Quinapril Hydrochloride RS in Diluent (USP 1-May-2021)

Standard solution: 5 µg/mL each of USP Quinapril Related Compound A RS and USP Quinapril Related Compound B RS in Diluent

System suitability

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

Suitability requirements

Resolution: NLT 1.75 between quinapril and quinapril related compound A; NLT 3.5 between quinapril and quinapril related compound B,

System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution (USP 1-May-2021)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of quinapril related compound A or quinapril related compound B in the portion of Quinapril Hydrochloride 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 from the Standard solution

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

C_U = concentration of Quinapril Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of any individual unspecified impurity in the portion of Quinapril Hydrochloride taken:

Result = (r_U/r_T) × 100

r_U = peak response of any individual unspecified impurity from the Sample solution

r_T = sum of the responses of all the peaks from the Sample solution

Acceptance criteria: See Table 1.

Table 1

6 SPECIFIC TESTS

Add the following:

6.1 Content of Acetone (if labeled as acetone solvate)

Solution A: Water

Solution B: Acetonitrile

Mobile phase: See Table 2.

Table 2

Standard solution: 1.0 mg/mL of USP Acetone RS in water prepared as follows. Weigh and transfer an appropriate amount of USP Acetone RS to a suitable volumetric flask containing 50% of the final volume of water. Dilute with water to volume.

Sample solution: 10 mg/mL of Quinapril Hydrochloride in water. Sonicate if necessary.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 264 nm

Column: 4.6-mm × 10-cm; 2.6-µm packing L1

Temperatures

Autosampler: 20°

Column: 35°

Flow rate: 2.0 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of acetone in the portion of Quinapril Hydrochloride as acetone solvate taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of acetone from the Sample solution

r_S = peak response of acetone from the Standard solution

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

C_U = concentration of Quinapril Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 7.9%–13.9% (USP 1-May-2021)

6.2 Water Determination 〈921〉, Method I: NMT 1.0%

6.3 Optical Rotation 〈781S〉, Procedures, Specific Rotation

Sample solution: 20 mg/mL in methanol

Acceptance criteria: +14.4° to +15.4°

7 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in well-closed containers, and store at controlled room temperature. If labeled as an acetone solvate, store in a tight container filled with nitrogen at controlled room temperature. (USP 1-May-2021)

Add the following:

Labeling: Where it is an acetone solvate form, the label so indicates. (USP 1-May-2021)

Change to read:

USP Reference Standards 〈11〉

USP Acetone RS (USP 1-May-2021)

USP Quinapril Hydrochloride RS

USP Quinapril Related Compound A RS

Ethyl [3S-[(2R*),3a,11ab]]-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-2021)

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-2021)

C₂₃H₂₆N₂O₅ 410.47