Iodixanol

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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C₃₅H₄₄I₆N₆O₁₅ 1550.18

1,3-Benzenedicarboxamide, 5,5′-[(2-hydroxy-1,3-propanediyl)bis(acetylimino)]bis[N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-;

5,5′-[(2-Hydroxytrimethylene)bis(acetylimino)]bis[N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide] CAS RN^®: 92339-11-2; UNII: HW8W27HTXX

1 DEFINITION

Iodixanol contains NLT 98.6% and NMT 101.0% of iodixanol (C₃₅H₄₄I₆N₆O₁₅), calculated on the anhydrous basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉, Infrared Spectroscopy: 197K

B. The retention times of the three principal peaks of the Sample solution correspond to those of the Identification solution, as obtained in the test for Limit of Iodixanol Related Compound E and Iodixanol Impurity H. [Note-A third isomer may appear as a minor peak.]

3 ASSAY

3.1 PROCEDURE

Sample solution:

Transfer 500 mg of Iodixanol to a glass-stoppered, 125-mL conical flask. Add 25 mL of 1.25 N sodium hydroxide and 500 mg of powdered zinc. Connect the flask to a reflux condenser, and reflux for 1 h. Cool the flask to room temperature, rinse the condenser with 20 mL of water, disconnect the flask from the condenser, and pass the mixture through a filter. Rinse the flask and the filter thoroughly with small portions of water, adding the rinsings to the filtrate. Add 5 mL of glacial acetic acid.

Titrimetric system

(See Titrimetry 〈541〉.)

Mode: Direct titration

Titrant: 0.1 N silver nitrate VS

Endpoint detection: Potentiometric

Analysis

Sample: Sample solution

Titrate the Sample solution with the Titrant.

Calculate the percentage of iodixanol (C₃₅H₄₄I₆N₆O₁₅) in the portion of Iodixanol taken:

Result = [(V × N × F) / W] × 100

V = sample titrant volume (mL)

N = Titrant normality (meq/mL)

F = equivalent weight of iodixanol, 258.4 mg/meq

W = weight of iodixanol (mg)

Acceptance criteria: 98.6%–101.0% on the anhydrous basis

4 IMPURITIES

4.1 LIMIT OF FREE IODIDE

Sample solution: 5 g of Iodixanol in 30 mL of water

Titrimetric system

(See Titrimetry 〈541〉.)

Mode: Direct titration

Titrant: 0.001 N silver nitrate VS

Endpoint detection: Potentiometric

Analysis

Calculate the percentage of free iodide in the portion of Iodixanol taken:

Result = [(V × N × F) / W] × 100

V = sample titrant volume (mL)

N = Titrant normality (meq/mL)

F = equivalent weight of iodide, 0.1269 mg/meq

W = weight of iodixanol (mg)

Acceptance criteria: NMT 0.001%

4.2 LIMIT OF FREE AROMATIC AMINE

[Note-Rinse all glassware with water.]

Standard solution: 4 µg/mL of sodium chloride in water

Sample solution: 2 g of Iodixanol in 100 mL of water

Acceptance criteria: The specific conductance in the Sample solution is NMT that of the Standard solution (equivalent to NMT 0.02% of ionic compounds, as sodium chloride).

4.3 LIMIT OF FREE AROMATIC AMINE

Solution A: 3 mg/mL of N-(1-naphthyl)ethylenediamine dihydrochloride in a mixture of propylene glycol and water (70:30)

Blank solution: Add 15 mL of water to a 25-mL volumetric flask.

Standard stock solution: 10 µg/mL of USP Iohexol Related Compound B RS in water

Standard solution: Transfer 10.0 mL of the Standard stock solution and 5 mL of water to a 25-mL volumetric flask.

Sample solution: Transfer 200 mg of Iodixanol to a 25-mL volumetric flask, and add 15 mL of water.

Instrumental conditions

Mode: UV-Vis

Analytical wavelength: 495 nm

Cell: 5 cm

Analysis

Samples: Blank solution, Standard solution, and Sample solution

Treat the Samples as follows. Place the flask in an ice bath for 5 min. Add 1.5 mL of 6 N hydrochloric acid, and mix by swirling. Add 1.0 mL of sodium nitrite solution (20 mg/mL), and allow to stand in the ice bath for 4 min. Remove the flask from the ice bath, add 1.0 mL of sulfamic acid solution (40 mg/mL), and swirl gently until gas evolution ceases.

[Caution-Considerable pressure is produced.]

Add 1.0 mL of Solution A, dilute with water to volume, and allow to stand for 5 min.

Measure the absorbance of the Standard solution and the Sample solution against the Blank solution.

Acceptance criteria: The absorbance of the Sample solution is NMT that of the Standard solution (NMT 0.05% of free aromatic amine).

4.4 LIMIT OF 2-METHOXYETHANOL

Internal standard solution: 0.01 mg/mL of secondary butyl alcohol in water

Standard stock solution: 0.005 mg/mL of methanol and 0.01 mg/mL (ERR 1-Mar-2022) each of isopropyl alcohol, secondary butyl alcohol, and 2-methoxyethanol in Internal standard solution

Standard solution: Transfer about 0.25 g of USP Iodixanol RS and 1.0 mL of Standard stock solution to a headspace vial and seal the vial with a septum and crimp cap.

Sample solution: Transfer about 0.25 g of Iodixanol and 1.0 mL of Internal standard solution to a headspace vial and seal the vial with a septum and crimp cap.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC with suitable headspace autosampler

Detector: Flame ionization

Column: 0.53-mm × 30-m fused-silica; coated with a 1-µm phase G16

Temperatures

Autosampler: 105°

Needle: 130°–140°

Injection port: 150°

Detector: 200°

Column: See Table 1

Table 1

Carrier gas: Helium

Flow rate: 11 mL/min

Injection volume: 1 mL of the headspace

System suitability

Sample: Standard solution

[Note-The typical relative retention times for methanol, isopropyl alcohol, secondary butyl alcohol, and 2-methoxyethanol are 0.5, 0.6, 1.0, and 1.9 respectively.]

Suitability requirements

Resolution: NLT 1.0 between methanol and isopropyl alcohol

Relative standard deviation: NMT 10.0% for the ratio of 2-methoxyethanol to internal standard

Analysis

Samples: Standard solution and Sample solution

Calculate the amount of 2-methoxyethanol in the portion of Iodixanol taken:

Result = (R_U/R_S) × (C_S/C_U)

R_U = peak response ratio of 2-methoxyethanol to the internal standard from the Sample solution

R_S = peak response ratio of 2-methoxyethanol to the internal standard from the Standard solution

C_S = concentration of 2-methoxyethanol in the Standard solution (µg/mL)

C_U = concentration of Iodixanol in Sample solution (g/mL)

Acceptance criteria: NMT 10 µg/g of 2-methoxyethanol

4.5 ORGANIC IMPURITIES

Solution A: Water

Solution B: Acetonitrile and water (50:50)

System suitability solution:

0.25 mg/mL of USP Iodixanol RS,

0.0025 mg/mL of USP Iodixanol Related Compound C RS, and

0.005 mg/mL of USP Iodixanol Related Compound D RS in water

Sample solution: 2.5 mg/mL of Iodixanol in water

Mobile phase: See Table 2

Table 2

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

Use the chromatogram from the System suitability solution to identify the peaks based on the relative retention times given in Table 3.

Suitability requirements

Resolution: NLT 1.5 between the two peaks due to iodixanol related compound D

Peak-to-valley ratio: NLT 1.3 between the first iodixanol peak and iodixanol related compound C (first peak)

Analysis

Sample: Sample solution

[Note-If iodixanol related compound C is present, only the first and larger peak with a retention time of 1.04 relative to the main iodixanol peak is seen between the two principal iodixanol peaks; the second iodixanol related compound C peak co-elutes with iodixanol. The area of the first and larger peak corresponds to approximately 80% of the total area of iodixanol related compound C. Determine the peak area of the first peak by drawing a vertical line through the minimum before the peak and a horizontal baseline at the minimum after the peak.]

Calculate the percentage of each impurity in the Sample solution:

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each impurity in the Sample solution

r_T = sum of all peak responses greater than 0.05% of the principal peaks in the Sample solution

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. Disregard any impurity less than or equal to 0.05%.

Table 3

4.6 LIMIT OF IODIXANOL RELATED COMPOUND E AND IODIXANOL IMPURITY H

Solution A: Acetonitrile and water (50:50)

Solution B: Acetonitrile

Mobile phase: See Table 4

Table 4

System suitability solution: 0.25 mg/mL of USP Iodixanol RS and 0.025 mg/mL of USP Iodixanol Related Compound E RS in water

Identification solution: 2.5 mg/mL of USP Iodixanol RS in water

Sample solution: 2.5 mg/mL of Iodixanol in water

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 25-cm; 5-µm packing L8

Flow rate: 1.7 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

[Note-See Table 5 for relative retention times.]

Suitability requirements

Resolution: NLT 5.0 between iodixanol related compound E (first peak) and iodixanol (first peak)

Analysis

Samples: Identification solution and Sample solution

[Note-Iodixanol related compound E exhibits two peaks, the second of which may partly overlap with one of iodixanol peaks; use only the area of the first and larger peak of iodixanol related compound E, which corresponds to approximately 60% of the total area of iodixanol related compound E.]

Use the chromatograms obtained from the Identification solution and Sample solution for Identification test B.

Calculate the percentage of iodixanol related compound E and iodixanol impurity H in the Sample solution:

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each impurity in the Sample solution

r_T = sum of all peak responses greater than 0.05% of the principal peaks in the Sample solution

F = relative response factor (see Table 5)

Acceptance criteria: See Table 5.

Table 5

ᵃ 5-[[3-[[3-[[[3-[[3-[3,5-bis-[[[2,3-Dihydroxypropyl]amino]carbonyl]-2,4,6-triiodophenyl]-2-hydroxypropyl](acetylimino)]-5-[[[2,3-dihydroxypropyl]amino]carbonyl]-2,4,6-triiodophenyl]carbonyl]amino]-2-hydroxypropyl]oxy]-2-hydroxypropyl](acetylimino)]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.

5 SPECIFIC TESTS

WATER DETERMINATION, Method I (921): NMT 4.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed, light-resistant containers. Store at room temperature.

USP REFERENCE STANDARDS (11)

USP lodixanol RS

USP lodixanol Related Compound C RS

5-[Acetyl[3-[[3,5-bis[[(2,3-dihydroxypropyl)amino]carbonyl]-2,4,6-triiodophenyl]amino]-2-hydroxypropyl]amino]N,N′-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.

C₃₃H₄₂I₆N₆O₁₄ 1508.15

USP Iodixanol Related Compound D RS

5-[Acetyl(2-hydroxy-3-methoxypropyl)amino]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.

C₂₀H₂₈I₃N₃O₉ 835.16

USP Iodixanol Related Compound E RS

(5-{N-[3-(N-{3-Carbamoyl-5-[(2,3-dihydroxypropyl)carbamoyl]-2,4,6-triiodophenyl}acetamido)-2-hydroxypropyl]acetamido}-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.

USP Iohexol Related Compound B RS

5-Amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide.

C₁₄H₁₈I₃N₃O₆ 705.02