Amiodarone Hydrochloride Injection

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

Amiodarone Hydrochloride Injection is a sterile solution of Amiodarone Hydrochloride. It contains NLT 90.0% and NMT 110.0% of the labeled amount of amiodarone hydrochloride (C₂₅H₂₉I₂NO₃·HCI). It may contain suitable preservatives.

2 IDENTIFICATION

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

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

3 ASSAY

3.1 PROCEDURE

Buffer: 1.36 g/L of potassium phosphate, monobasic in water prepared as follows. To 1.36 g of potassium phosphate, monobasic in a 1-L volumetric flask add about 900 mL of water and 1 mL of triethylamine. Adjust with phosphoric acid to a pH of 6.0. Dilute with water to volume.

Mobile phase: Acetonitrile and Buffer (80:20)

Diluent: Acetonitrile and water (60:40)

Standard solution: 0.025 mg/mL of USP Amiodarone Hydrochloride RS in Diluent

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Column: 4.6-mm x 10-cm; 5-µm packing L1

Flow rate: 2 mL/min

Injection volume: 20 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

3.4 Analysis

Calculate the percentage of the labeled amount of amiodarone hydrochloride (C₂₅H₂₉I₂NO₃·HCI) in the portion of Injection taken:

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

r_U = peak response of amiodarone from the Sample solution

r_S = peak response of amiodarone from 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: 90.0%-110.0%

4 OTHER COMPONENTS

CONTENT OF BENZYL ALCOHOL (if present)

Internal standard solution: 1 mg/mL of phenol in isopropyl alcohol

Standard stock solution: 1.6 of mg/mL of USP Benzyl Alcohol RS in isopropyl alcohol

Standard solution: 0.2 mg/mL of phenol and 0.19 mg/mL of USP Benzyl Alcohol RS in isopropyl alcohol from the Internal standard solution and the Standard stock solution

Sample stock solution: Nominally 1.6 mg/mL of benzyl alcohol in isopropyl alcohol from Injection

Sample solution: Nominally 0.2 mg/mL of phenol and 0.19 mg/mL of benzyl alcohol in isopropyl alcohol from the Internal standard solution and the Sample stock solution

Blank: 0.2 mg/mL of phenol in isopropyl alcohol from the Internal standard solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.32-mm x 30-m fused silica capillary; coated with 1-µm film of phase G16

Temperatures

Injection port: 200°

Column: 150°

Detector: 200°

Carrier gas: Nitrogen

Flow rate: 10 mL/min

Injection volume: 1 µL

Injection type: Split; split ratio, 10:1

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0% for the peak response ratio of benzyl alcohol to phenol

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of benzyl alcohol in the portion of Injection taken:

Result = (R_U/R_S) x (C_S/C_U) x 100

R_U = peak response ratio of benzyl alcohol to phenol from the Sample solution

R_S = peak response ratio of benzyl alcohol to phenol from the Standard solution

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

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

FICIAL

Acceptance criteria: 90.0%-110.0%

5 IMPURITIES

Change to read:

5.1 LIMIT OF IODIDE

Use freshly prepared solutions in amber glassware.

Amiodarone stock solution: Nominally 5 mg/mL of amiodarone hydrochloride in water from Injection

Potassium iodide solution: 88.2 µg/mL of potassium iodide in water

Potassium iodate solution: 10.7 g/L of potassium iodate (ERR 1-Jul-2021) in water

Standard solution: 4.41 µg/mL of potassium iodide prepared as follows. Into a suitable flask pipet 15.0 mL of Amiodarone stock solution, 1.0 mL of 0.1 N hydrochloric acid, 1.0 mL of Potassium iodide solution, 1.0 mL of Potassium iodate solution, and 2.0 mL of water. Mix, and allow to stand for 4 h. Protect from light.

Sample solution: Nominally 3.75 mg/mL of amiodarone hydrochloride prepared as follows. Into a suitable flask pipet 15.0 mL of Amiodarone stock solution, 1.0 mL of 0.1 N hydrochloric acid, 1.0 mL of Potassium iodate solution, and 3.0 mL of water. Mix, and allow to stand for 4 h. Protect from light.

Blank: Into a suitable flask pipet 15.0 mL of Amiodarone stock solution, 1.0 mL of 0.1 N hydrochloric acid, and 4.0 mL of water. Mix, and allow to stand for 4 h. Protect from light.

Instrumental conditions

Mode: Vis

Analytical wavelength: 420 nm

Cell: 1 cm

Analysis

Samples: Standard solution, Sample solution, and Blank

Calculate the amount of iodide, in ppm, in the portion of Injection taken:

Result = (A_U - A_B)/[(A_S - A_B) - (A_U - A_B)] x (C_S/C_U) x (M_r1/M_r2)

A_U = absorbance of the Sample solution

A_B = absorbance of the Blank

A_S = absorbance of the Standard solution

C_S = concentration of potassium iodide in the Standard solution (µg/mL)

C_U = nominal concentration of amiodarone hydrochloride in the Sample solution (g/mL)

M_r1 = molecular weight of iodide, 126.90

M_r2 = molecular weight of potassium iodide, 166.00

Acceptance criteria: NMT 250 ppm

5.2 ORGANIC IMPURITIES

Buffer: Add 3 mL of acetic acid, glacial to 800 mL of water. Adjust with ammonia TS to a pH of 4.9. Dilute with water to 1000 mL.

Mobile phase: Acetonitrile, methanol, and Buffer (40:30:30)

Diluent: Acetonitrile, methanol, and water (50:30:20)

Standard stock solution A: 0.2 mg/mL of USP Amiodarone Hydrochloride RS in Diluent

Standard stock solution B: 0.4 mg/mL of USP Amiodarone Related Compound E RS in Diluent

Standard solution: 1 µg/mL of USP Amiodarone Hydrochloride RS, 30 µg/mL of USP Amiodarone Related Compound D RS, and 2 µg/mL of USP Amiodarone Related Compound E RS in Diluent prepared as follows. Transfer a suitable quantity of USP Amiodarone Related Compound D RS to a suitable volumetric flask, and add a suitable amount of Standard stock solution A and Standard stock solution B. Dilute with Diluent to volume.

Sample solution: Nominally 1 mg/mL of amiodarone hydrochloride in Diluent from a suitable volume of Injection

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

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

Temperatures

Autosampler: 2°-8°

Column : 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention time of amiodarone for the Standard solution, and NLT 2 times the retention time of amiodarone for

the Sample solution

System suitability

Sample: Standard solution

[NOTE-See Table 1 for relative retention times.]

Suitability requirements

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

Tailing factor: NMT 2.0 for the amiodarone, amiodarone related compound D, and amiodarone related compound E peaks

Relative standard deviation: NMT 5.0% for the amiodarone, amiodarone related compound D, and amiodarone related compound E peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of amiodarone related compound D or amiodarone related compound E in the portion of Injection taken:

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

r_U = peak response of amiodarone related compound D or amiodarone related compound E from the Sample solution

r_S = peak response of amiodarone related compound D or amiodarone related compound E from the Standard solution

C_S = concentration of USP Amiodarone Related Compound D RS or USP Amiodarone Related Compound E RS in the Standard solution (mg/mL)

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

Calculate the percentage of any unspecified degradation product in the portion of Injection taken:

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

r_U = peak response of amiodarone from the Standard solution

r_S = peak response of any unspecified degradation product from the Sample 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: See Table 1.

Table 1

6 SPECIFIC TESTS

6.1 BACTERIAL ENDOTOXINS TEST (85)

Meets the requirements

6.2 STERILITY TESTS (71)

Meets the requirements

6.3 PH (791)

3.0-5.0

6.4 PARTICULATE MATTER IN INJECTIONS (788)

Meets the requirements for small-volume injections

6.5 OTHER REQUIREMENTS

Meets the requirements in Injections and Implanted Drug Products (1).

7 ADDITIONAL REQUIREMENTS

7.1 PACKAGING AND STORAGE

Preserve in single-dose or multiple-dose glass containers, protected from light and excessive heat. Store at controlled room temperature.

7.2 LABELING

Label it to indicate that it is to be diluted to the appropriate strength with a suitable parenteral vehicle prior to administration. Label it to indicate the type and amount of preservative used. Label it to indicate that it is preservative free, if no preservative is present.

7.3 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 Benzyl Alcohol RS