Amiodarone 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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C₂₅H₂₉I₂NO₃·HCI 681.77

Methanone, (2-butyl-3-benzofuranyl) (4-[2-(diethyl amino)ethoxy]-3,5-diiodophenyl]-hydrochloride;

2-Butyl-3-benzofuranyl 4-[2-(diethylamino) ethoxy]-3,5-diiodophenyl ketone hydrochloride CAS RN^®: 19774-82-4; UNII: 976728SY6Z.

2-Butyl-3-benzofuranyl 4-[2-(diethylamino) ethoxy]-3,5-diiodophenyl ketone CAS RN^®: 1951-25-3; UNII: N3RQ532IUT.

1 DEFINITION

Amiodarone Hydrochloride contains NLT 98.5% and NMT 101.0% of C₂₅H₂₉I₂NO₃·HCI, calculated on the dried basis.

2 IDENTIFICATION

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

B. IDENTIFICATION TESTS-GENERAL, Chloride (191): Meets the requirements

3 ASSAY

3.1 PROCEDURE

Buffer: Dissolve 6.80 g of monobasic potassium phosphate in 900 mL of water, and add 1.0 mL of triethylamine. Adjust with phosphoric acid to a pH of 6.00 ± 0.05, and dilute with water to 1000 mL.

Diluent: Acetonitrile and water (1:1)

Mobile phase: Acetonitrile and Buffer (1:1)

Standard stock solution: 0.5 mg/mL of USP Amiodarone Hydrochloride RS in methanol

Standard solution: 0.1 mg/mL USP Amiodarone Hydrochloride RS in Diluent from Standard stock solution

Sample stock solution: 0.5 mg/mL of Amiodarone Hydrochloride in methanol

Sample solution: 0.1 mg/mL of Amiodarone Hydrochloride in Diluent from Sample stock solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 3.9-mm x 15-cm; 5-µm packing L26

Flow rate: 1.5 mL/min

Injection size: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Column efficiency: NLT 1000 theoretical plates

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of C₂₅H₂₉I₂NO₃·HCI in the portion of Amiodarone Hydrochloride taken:

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

r_U = peak response of amiodarone in the Sample solution

r_S = peak response of amiodarone in the Standard solution

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

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

Acceptance criteria: 98.5%-101.0%, on the dried basis

4 IMPURITIES

4.1 INORGANIC IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1% on a 1-g sample

4.2 ORGANIC IMPURITIES

[NOTE-The product meets the requirements for both Procedure 1 and Procedure 2.]

4.2.1 PROCEDURE 1

Potassium iodobismuthate solution: Dissolve 100 g of tartaric acid in 400 mL of water, and add 8.5 g of Bismuth subnitrate. Shake for 1 h, add 200 mL of a 400 g/L solution of potassium iodide, and shake well. Allow to stand for 24 h, filter, and protect from light.

Standard solution A: 0.02 mg/mL of USP Amiodarone Related Compound H. RS in methylene chloride

Standard solution B: Standard solution A and Sample solution (1:1).

Sample solution: 100 mg/mL of Amiodarone Hydrochloride in methylene chloride

Chromatographic system

(See Chromatography (621), Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: Suitable layer of chromatographic silica gel and fluorescent indicator with maximum absorbance at 254 nm

Application volume

Standard solution A: 50 µL

Standard solution B: 100 µL

Sample solution: 50 µL

Developing solvent system: Methylene chloride, methanol, and anhydrous formic acid (17:2:1)

Analysis

Samples: Standard solution A, Standard solution B, and Sample solution

Develop the plate in the Developing solvent system until the solvent front has moved NLT two-thirds the length of the plate, and dry in a current of cold air. Spray the plate with Potassium iodobismuthate solution and then with 3% Hydrogen peroxide solution. Examine immediately in daylight: the spot from Standard solution B due to amiodarone related compound H is clearly visible.

Acceptance criteria: Any spot with the same R, as the spot due to amiodarone related compound H from the Sample solution is not more intense than the spot from Standard solution A (0.02%).

4.2.2 PROCEDURE 2

Buffer: Add 3 mL of glacial acetic acid to 800 mL of water. Adjust with diluted ammonia solution to a pH of 4.9, and dilute with water to 1000 mL.

Mobile phase: Acetonitrile: methanol: Buffer (4:3:3 v/v/v).

Diluent: Acetonitrile and water (1:1)

Standard stock solution: Dissolve equal quantities of USP Amiodarone Related Compound D RS, USP Amiodarone Related Compound E RS, and USP Amiodarone Hydrochloride RS in a known amount of methanol.

Standard solution: 0.01 mg/mL each of USP Amiodarone Related Compound D RS, USP Amiodarone Related Compound E RS, and USP Amiodarone Hydrochloride RS, in Diluent from Standard stock solution

Sample solution: 5 mg/mL of Amiodarone Hydrochloride in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

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

Column temperature: 30°

Flow rate: 1 mL/min

Injection size: 10 µL

Run time: 2 times the retention time of amiodarone

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 3.5 between amiodarone related compound D and amiodarone related compound E

Analysis

[NOTE-Disregard any peak that is less than 0.05%.]

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Amiodarone Hydrochloride taken:

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

r_U = peak response of each impurity in the Sample solution

r_S = peak response of amiodarone in the Standard solution

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

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

Acceptance criteria

Individual impurities: See Impurity Table 1.

Total impurities: NMT 0.5%

Impurity Table 1

^a (2-Butylbenzofuran-3-yl){4-[2-(diethylamino)ethoxy]phenyl}methanone.

^b (2-Butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone.

^c (2-Butylbenzofuran-3-yl)(4-hydroxyphenyl)methanone.

^d (2-Butylbenzofuran-3-yl){4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl}methanone.

^e (2-Butylbenzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3-iodophenyl}methanone.

^f [2-[(1RS)-1-Methoxybutyl]benzofuran-3-yl][4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone.

^g (2-Butylbenzofuran-3-yl)(4-hydroxy-3-iodophenyl)methanone.

5 SPECIFIC TESTS

5.1 LIMIT OF IODIDES

Solution A: Add 1.50 g of Amiodarone Hydrochloride to 40 mL of water at 80°, and shake until completely dissolved. Cool, and dilute with water to 50.0 mL.

Standard solution: To 15.0 mL of Solution A add 1.0 mL of 0.1 M hydrochloric acid, 1.0 mL of an 88.2 mg/L solution of potassium iodide, and 1.0 mL of 0.05 M potassium iodate. Dilute with water to 20.0 mL. Allow to stand protected from light for 4 h.

Sample solution: To 15.0 mL of Solution A add 1.0 mL of 0.1 M hydrochloric acid and 1.0 mL of 0.05 M potassium iodate. Dilute with water to 20.0 mL. Allow to stand protected from light for 4 h.

Analysis: Measure the absorbances of the Standard solution and the Sample solution at 420 nm, using a mixture of 15.0 mL of Solution A and 1.0 mL of 0.1 M hydrochloric acid diluted with water to 20.0 mL to serve as the blank. The absorbance of the Sample solution is NMT half the absorbance of the Standard solution.

Acceptance criteria: NMT 150 ppm

5.2 PH (791)

3.2-3.8. Dissolve 1 g of Amiodarone Hydrochloride in water by heating at 80°. Cool, and dilute with water to 20 mL..

5.3 LOSS ON DRYING (731)

Use 1 g of sample, and dry under vacuum (NMT 0.3 kPa) at 50° for 4 h: it loses NMT 0.5% of its weight.

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in light-resistant, tight containers. Store at controlled room temperature.

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Amiodarone Hydrochloride RS

USP Amiodarone Related Compound D RS

(2-Butylbenzofuran-3-yl) (4-hydroxy-3,5-diiodophenyl) methanone.

C₁₉H₁₆I₂O₃ 546.14

USP Amiodarone Related Compound E RS

(2-Butylbenzofuran-3-yl) (4-hydroxyphenyl) methanone.

C₁₉H₁₈O₃ 294.34

USP Amiodarone Related Compound H RS

2-Chloro-N,N-diethylethanamine hydrochloride (ERR 1-Dec-2020).

C₆H₁₄CIN·HCI 172.09 (ERR 1-Dec-2020)