Iohexol 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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To view the Notice from the Expert Committee that posted in conjunction with this accelerated revision, please click www.uspnf.com/rb-johexol-inj-20230331.

1 DEFINITION

lohexol Injection is a sterile solution of lohexol in Water for Injection. It contains NLT 95.0% and NMT 105.0% of the labeled amount of Iohexol (C₁₉H₂₆I₃N₃O₉) as organically bound iodine. It may contain small amounts of suitable buffers and Edetate Calcium Disodium as a stabilizer.

lohexol Injection intended for intravascular or intrathecal use contains no antimicrobial agents.

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution correspond to those of the System suitability solution, as obtained in the test for Organic Impurities.

3 ASSAY

3.1 PROCEDURE

Sample: A volume of Injection equivalent to 300 mg of iodine

Analysis: Transfer the Sample to a glass-stoppered, 250-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 the solution for 1 h. Cool the flask to room temperature, rinse the condenser with 20 mL of water, disconnect the flask from the condenser, and filter the mixture. Rinse the flask and the filter thoroughly with small portions of water, adding the rinsings to the filtrate. Add 5 mL of glacial acetic acetic acid, and titrate with 0.1 N silver nitrate VS. Each mL of 0.1 N silver nitrate is equivalent to 27.37mg of C₁₉H₂₆I₃N₃O₉

Acceptance criteria: 95.0%-105.0%

4 IMPURITIES

4.1 ORGANIC IMPURITIES

Solution A: Acetonitrile

Solution B: Water

Mobile phase: The percentage of Solution A increases from 1% to 13% at a rate of 0.2%/min.

System suitability solution: 1.5 mg/mL, 0.0075 mg/mL, and 0.0069 mg/mL each of USP lohexol RS, USP lohexol Related Compound A RS, and USP lohexol Related Compound C RS in water

Sample solution: 1.5 mg/mL of lohexol

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm stainless steel column; packing L1

Flow rate: 1.0 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

[NOTE-The relative retention times for the exo-isomer of iohexol and the O-alkylated compounds are 1.0 and between 1.1 and 1.4, respectively.]

[NOTE-The peak area of iohexol related compound C is 0.5% ± 0.1% compared to the total area of all the peaks in the chromatogram.]

Suitability requirements

Resolution: NLT 20.0 between iohexol related compound A and iohexol related compound C

Analysis

Sample: Sample solution

Excluding peaks with retention times between 0.84 (relative to the endo-isomer of iohexol, which is the first main peak) and 1.0, calculate the percentage of O-alkylated compounds and any other individual impurity peak, in the portion of lohexol taken:

Result = (r_U/r_T) × 100

r_U = peak response of each impurity

r_T = sum of all the peak responses

Acceptance criteria

Individual impurity: NMT 0.6% of O-alkylated compounds; NMT 0.1% of any other individual impurity

Total impurities: NMT 0.3%, excluding O-alkylated compounds

5 SPECIFIC TESTS

BACTERIAL ENDOTOXINS TEST (85): NMT 0.2 USP Endotoxin Unit per 50 mg of iodine

PH (791): 6.8-7.7

PARTICULATE MATTER IN INJECTIONS (788): The Injection labeled for intrathecal use meets the requirements for small-volume injections.

FREE IODIDE: Transfer 5.0 mL of Injection to a suitable container, add 20 mL of water, and titrate with 0.001 N silver nitrate VS using a silver electrode in combination with an appropriate reference electrode. Each mL of 0.001 N silver nitrate is equivalent to 0.1269 mg of iodine.

Acceptance criteria: NMT 0.02%, based on the content of iohexol

INJECTIONS AND IMPLANTED DRUG PRODUCTS (1): Meets the requirements

6 ADDITIONAL REQUIREMENTS

Change to read:

PACKAGING AND STORAGE: Preserve Injection intended for intravascular or intrathecal use in single-dose or multiple-dose plastic or preferably (RB 1-Apr-2023) Type I glass containers. Store at controlled room temperature, protected from light. Do not freeze.

LABELING: Label containers of Injection to direct the user to discard any unused portion. The labeling states also that it is not to be used if it is discolored or contains a precipitate. Label it also to state its routes of administration. When the specific dose strength is not intended for intrathecal use, label it to indicate "serious injury can occur if given by intrathecal route".

USP REFERENCE STANDARDS (11)

USP lohexol RS

USP lohexol Related Compound A RS

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

USP lohexol Related Compound C RS

N,N'-Bis(2,3-dihydroxypropyl)-5-nitro-1,3-benzenedicarboxamide.