Perindopril Erbumine

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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C₁₉H₃₂N₂O₅·C₄H₁₁N 441.60(USP 1-Aug-2022)

1H-Indole-2-carboxylic acid, 1-[2-[[1-(ethoxycarbonyl)butyl)amino]-1-oxopropyl]octahydro-, [2S-[1[R*(R*)],2α,3aβ,7aβ]]-, compound with 2-methyl-2-propanamine (1:1);

(2S,3aS,7aS)-1-[(S)-N-[(S)-1-Carboxybutyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1);

2-Methylpropan-2-amine (2S,3aS,7aS)-1-{[(S)-1-ethoxy-1-oxopentan-2-yl]-L-alanyl}octahydro-1H-indole-2-carboxylate(USP 1-Aug-2022) CAS RN^®: 107133-36-8; UNII: 1964X464OJ.

1 DEFINITION

Perindopril Erbumine contains NLT 98.0% and NMT 102.0% of perindopril erbumine (C₁₉H₃₂N₂O₅·C₄H₁₁N), calculated on the anhydrous basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

B. The retention time of the major peak of the Sample solution corresponds to that of System suitability solution 1, as obtained in the test for Limit of Perindopril Related Compound I.

3 ASSAY

3.1 PROCEDURE

Buffer: Dissolve 0.92 g of sodium 1-heptanesulfonate in 1 L of water and add 1 mL of triethylamine. Adjust with a solution of perchloric acid and water (1:1) to a pH of 2.0.

Mobile phase: Acetonitrile and Buffer (35:65)

Standard solution: 0.1 mg/mL of USP Perindopril Erbumine RS in Buffer. Initially add Buffer to about 60% of the flask volume, sonicate to dissolve, and dilute with Buffer to volume.

Sample solution: 0.1 mg/mL of Perindopril Erbumine in Buffer. Initially add Buffer to about 60% of the flask volume, sonicate to dissolve, and dilute with Buffer to volume.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7

Column temperature: 60°

Flow rate: 1 mL/min

Injection volume: 20 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.5%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of perindopril erbumine (C₁₉H₃₂N₂O₅·C₄H₁₁N) in the portion of Perindopril Erbumine taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak area of perindopril from the Sample solution

r_S = peak area of perindopril from the Standard solution

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

C_U = concentration of Perindopril Erbumine in the Sample solution (mg/mL)

Acceptance criteria: 98.0%-102.0% on the anhydrous basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

Change to read:

4.2 ORGANIC IMPURITIES

Solution A: Proceed as directed for the Buffer as described in the Assay.

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Solution B and Solution A (20:80)

System suitability stock solution A: 0.03 mg/mL of USP Imidazole RS in Diluent

System suitability stock solution B: 0.03 mg/mL each of USP Perindopril Erbumine RS, USP Perindopril Related Compound B RS, USP Perindopril Related Compound C RS, USP Perindopril Related Compound D RS, and USP Perindopril Related Compound F RS in Diluent

System suitability solution: Transfer 5 mL each of System suitability stock solution A and System suitability stock solution B to a 50-mL volumetric flask and dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size, discard the first 3 mL of the filtrate, and use the clear filtrate.

Standard stock solution: 0.03 mg/mL of USP Perindopril Erbumine RS in Diluent prepared as follows. Dissolve a suitable quantity of USP Perindopril Erbumine RS in 80% of the total volume of Diluent, sonicate for about 5 min, and dilute with Diluent to volume.

Standard solution: 0.003 mg/mL of USP Perindopril Erbumine RS in Diluent from the Standard stock solution. Pass through a suitable filter of 0.45-µm pore size and discard the first 3 mL of the filtrate.

Sample solution: 3 mg/mL of Perindopril Erbumine in Diluent prepared as follows. Dissolve a suitable quantity of Perindopril Erbumine in 80% of the total volume of Diluent, sonicate for 5 min, and dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size and discard the first 3 mL of the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.0-mm × 25-cm; 4-µm packing L7

Column temperature: 60°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

Suitability requirements

Tailing factor: NMT 1.5 for the perindopril peak

Relative standard deviation: NMT 5.0% for the perindopril peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Perindopril Erbumine taken:

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of perindopril (USP 1-Aug-2022) from the Standard solution

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

C_U = concentration of Perindopril Erbumine in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.(USP 1-Aug-2022)

Table 2

^a Imidazole is quantitated using the test for Limit of Perindopril Related Compound A and Imidazole and is included in the table for identification purposes only.

^b (2S,3aS,7aS)-1-{(S)-2-[(S)-1-isopropoxy-1-oxopentan-2-ylamino]propanoyl}octahydro-1H-indole-2-carboxylic acid.

^c (2S,3aS,7aS)-1-[(2S)-2-(3-Cyclohexyl-2,4-dioxo-5-propylimidazolidin-1-yl)propanoyl]octahydro-1H-indole-2-carboxylic acid.

^d Total impurities include all specified and unspecified impurities and imidazole from the test for Limit of Perindopril Related Compound A and Imidazole. Perindopril related compound A is not included.

Change to read:

4.3 LIMIT OF PERINDOPRIL RELATED COMPOUND A AND IMIDAZOLE

Buffer: Dissolve 1.84 g of sodium 1-heptanesulfonate and 5.23 g of dibasic potassium phosphate in 1 L of water. Add 1 mL of triethylamine and adjust the pH of the solution with phosphoric acid to 2.0.

Solution A: Acetonitrile and Buffer (17:83)

Solution B: Acetonitrile and Buffer (60:40)

Solution C: Dissolve 0.74 g of tert-butylamine in 100 mL of water.

Mobile phase: See Table 3.

Table 3

Diluent: Solution A

Standard stock solution: 0.25 mg/mL of USP Perindopril Related Compound A RS and 0.1 mg/mL of USP Imidazole RS in Diluent. Sonicate if necessary.

Standard solution: 0.025 mg/mL of USP Perindopril Related Compound A RS and 0.01 mg/mL of USP Imidazole RS in Diluent prepared as follows. Transfer 1.0 mL of the Standard stock solution to a 10-mL volumetric flask. Add 2.5 mL of Solution C. Dilute with Diluent to volume. (USP 1-Aug-2022)

Sample solution: 10 mg/mL of Perindopril Erbumine in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detectors

Perindopril related compound A: UV 210 nm

Imidazole: UV 225 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7

Temperatures

Column: 60°

Autosampler: (USP 1-Aug-2022) 5°

Flow rate: 1 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for imidazole and perindopril related compound A are 1.0 and 1.5, (USP 1-Aug-2022) respectively.]

Suitability requirements

Tailing factor: NMT 1.8 for imidazole and perindopril related compound A, respectively (USP 1-Aug-2022)

Relative standard deviation: NMT 5.0% for imidazole and perindopril related compound A, respectively (USP 1-Aug-2022)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of perindopril related compound A or imidazole in the portion of Perindopril Erbumine taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of perindopril related compound A or imidazole from the Sample solution

r_S = peak response of perindopril related compound A or imidazole from the Standard solution

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

C_U = concentration of Perindopril Erbumine in the Sample solution (mg/mL)

Acceptance criteria

Perindopril related compound A: NMT 0.25%

Imidazole: NMT 0.1%

Change to read:

4.4 LIMIT OF PERINDOPRIL RELATED COMPOUND I

(USP 1-Aug-2022)

Solution A: Dissolve 5 g of potassium phosphate monobasic in 1900 mL of water. Adjust with triethylamine to a pH of 6.50 and add 100 mL of acetonitrile.

Solution B: Acetonitrile

Mobile phase: See Table 4.

Table 4

Diluent: Solution B and Solution A (17:83)

System suitability solution 1: 3 mg/mL of USP Perindopril Erbumine RS in Diluent. [NOTE-This solution is used in Identification test B.]

System suitability solution 2: 3 µg/mL of USP Perindopril Erbumine RS (USP 1-Aug-2022) from System suitability solution 1 and 6 µg/mL of USP Perindopril Related Compound I RS in Diluent (USP 1-Aug-2022)

Sample solution: 3 mg/mL of Perindopril Erbumine in Diluent prepared as follows. Dissolve a suitable quantity of Perindopril Erbumine in 80% of the total volume of Diluent, sonicate for 5 min, and dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size and discard the first 3 mL of filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

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

Column temperature: 60°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution 2

[NOTE-The relative retention times for perindopril and perindopril related compound I are 1.0 and 1.6, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for perindopril (USP 1-Aug-2022)

Relative standard deviation: NMT 5.0% for perindopril (USP 1-Aug-2022)

Analysis

Samples: System suitability solution 1 and (USP 1-Aug-2022) Sample solution

[NOTE-System suitability solution 1 is used in Identification B. (USP 1-AUG-2022)

Calculate the percentage of perindopril related compound I in the portion of Perindopril Erbumine taken:

Result = (r_U/r_T) × 100

r_U = peak response of perindopril related compound I from the Sample solution

r_T = total of all peak responses from the Sample solution

Acceptance criteria: NMT 0.1%

5 SPECIFIC TESTS

5.1 WATER DETERMINATION (921), Method la

NMT 1.0%; 3.00%-4.50% for the monohydrate

5.2 OPTICAL ROTATION (781S), Specific Rotation

Sample solution: 10 mg/mL of Perindopril Erbumine in ethanol

Acceptance criteria: -66° to -69°, at 20°

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in tight containers at controlled room temperature.

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Imidazole RS

USP Perindopril Erbumine RS

USP Perindopril Related Compound A RS

(2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid.

C₉H₁₅NO₂ 169.22

USP Perindopril Related Compound B RS

(2S,3aS,7aS)-1-{(S)-2-[(S)-1-Carboxybutylamino]propanoyl}octahydro-1H-indole-2-carboxylic acid monohydrate. (USP 1-Aug-2022)

C₁₇H₂₈N₂O₅·H₂O(USP 1-Aug-2022) 358.44 (USP 1-Aug-2022)

USP Perindopril Related Compound C RS

(S)-2-{(3S,5aS,9aS,10aS)-3-Methyl-1,4-dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl}pentanoic acid.

C₁₇H₂₆N₂O₄ 322.41(USP 1-Aug-2022)

USP Perindopril Related Compound D RS

(S)-2-{(3S,5aS,9aS,10aR)-3-Methyl-1,4-dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl}pentanoic acid.

C₁₇H₂₆N₂O₄ 322.41 (USP 1-Aug-2022)

USP Perindopril Related Compound F RS

(S)-Ethyl 2-{(3S,5aS, 9aS,10aS)-3-methyl-1,4-dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl}pentanoate.

C₁₉H₃₀N₂O₄ 350.46

USP Perindopril Related Compound I RS

2-Methylpropan-2-amine (2S,3aS,7aS)-1-{(S)-2-[(R)-1-ethoxy-1-oxopentan-2-ylamino]propanoyl}octahydro-1H-indole-2-carboxylate.

C₁₉H₃₂N₂O₅·C₄H₁₁N 441.60 (USP 1-Aug-2022)