Ondansetron 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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1 DEFINITION

Ondansetron Hydrochloride contains NLT 98.0% and NMT 102.0% of ondansetron hydrochloride (C₁₈H₁₉N₃O · HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: ▲197A, 197K, or▲ (USP 1-Aug-2024) 197M

B. Identification Tests—General 〈191〉, Chemical Identification Tests, Chloride

Sample solution: Dissolve 20 mg in 2 mL of water, add 1 mL of 2 M nitric acid, and ￾lter.

Acceptance criteria: Meets the requirements.

Add the following:

▲• C. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.▲ (USP 1-Aug-2024)

3 ASSAY

Change to read:

Procedure

▲Solution A: 2.4 g/L of monobasic sodium phosphate, anhydrous and 0.6 g/L of sodium 1-heptanesulfonate in water. Adjust with 0.5 N sodium hydroxide to a pH of 5.4.

Solution B: Acetonitrile

Mobile phase: See Table 1.▲

Table 1

Diluent: Acetonitrile and water (30:70). To each liter of this solution, add 1 mL of formic acid.

Standard solution: 0.1 mg/mL of USP Ondansetron Hydrochloride RS in Diluent

Sample solution: 0.1 mg/mL of Ondansetron Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 216 nm

Column: 4.6-mm × 25-cm; 5-μm packing L11

Temperatures

Autosampler: 15°

Column: 40°

Flow rate: 1 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73% ▲ (USP 1-Aug-2024)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ondansetron hydrochloride (C₁₈H₁₉N₃O · HCl) in the portion of Ondansetron Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of ondansetron from the Sample solution

rₛ = peak response of ondansetron from the Standard solution

Cₛ = concentration of USP Ondansetron Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = concentration of Ondansetron Hydrochloride in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Delete the following:

▲• Organic Impurities, Method I▲ (USP 1-Aug-2024)

Add the following:

▲• Limit of Methylene Bisondansetron

Buffer: 2.4 g/L of monobasic sodium phosphate, anhydrous in water. Adjust with 0.5 N sodium hydroxide to a pH of 6.5.

Mobile phase: Acetonitrile and Buffer (65:35)

Peak identi￾cation solution: 1 mg/mL of USP Ondansetron Resolution Mixture RS in Mobile phase

Standard solution: 0.002 mg/mL of USP Ondansetron Hydrochloride RS in Mobile phase

Sensitivity solution: 0.001 mg/mL of USP Ondansetron Hydrochloride RS from the Standard solution in Mobile phase

Sample solution: 1.0 mg/mL of Ondansetron Hydrochloride in Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 216 nm

Column: 4.6-mm × 25-cm; 5-μm packing L10

Temperatures

Autosampler: 15°

Column: 35°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: NLT 5 times the retention time of ondansetron

System suitability

Samples: Standard solution and Sensitivity solution

[Note—The relative retention times for ondansetron and methylene bisondansetron are 1.0 and 3.7, respectively. These relative retention times are provided as information that could aid in peak assignment.]

Suitability requirements

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of methylene bisondansetron in the portion of Ondansetron Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1/F) × 100

rᵤ = peak response of methylene bisondansetron from the Sample solution

rₛ = peak response of ondansetron from the Standard solution

Cₛ = concentration of USP Ondansetron Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = concentration of Ondansetron Hydrochloride in the Sample solution (mg/mL)

F = relative response factor, 0.75

Acceptance criteria: NMT 0.4% ▲ (USP 1-Aug-2024)

Delete the following:

▲• Organic Impurities, Method II▲ (USP 1-Aug-2024)

Delete the following:

▲• Limit of Ondansetron Related Compound D▲ (USP 1-Aug-2024)

Add the following:

▲• Organic Impurities

Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 1 mg/mL of USP Ondansetron Hydrochloride RS and 0.001 mg/mL of USP Ondansetron Related Compound G in Diluent

Standard solution: 0.001 mg/mL each of USP Ondansetron Hydrochloride RS and USP Ondansetron Related Compound D RS, and 0.002 mg/mL of USP Imidazole RS in Diluent

Sensitivity solution: 0.5 μg/mL each of USP Ondansetron Hydrochloride RS and USP Ondansetron Related Compound D RS, and 0.001 mg/mL of USP Imidazole RS from the Standard solution in Diluent

Sample solution: 1.0 mg/mL of Ondansetron Hydrochloride in Diluent

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note—The relative retention times in Table 2 are provided as information that could aid in peak assignment.]

Table 2

ᵃ 2-Methyl-1H-imidazole.

ᵇ 3-[(Dimethylamino)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one.

ᶜ 9-Methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one.

ᵈ Disregard the peak corresponding to methylene bisondansetron. Quantified in the test for Limit of Methylene Bisondansetron.

Suitability requirements

Resolution: NLT 2.0 between ondansetron and ondansetron related compound G, System suitability solution

Relative standard deviation: NMT 5.0% for ondansetron, Standard solution

Signal-to-noise ratio: NLT 10 for ondansetron, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ondansetron related compound D or imidazole in the portion of Ondansetron Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of ondansetron related compound D or imidazole from the Sample solution

rₛ = peak response of ondansetron related compound D or imidazole from the Standard solution

Cₛ = concentration of USP Ondansetron Related Compound D RS or USP Imidazole RS in the Standard solution (mg/mL)

Cᵤ = concentration of Ondansetron Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of any other specified or unspecified impurity in the portion of Ondansetron Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1/F) × 100

rᵤ = peak response of any other specified or unspecified impurity from the Sample solution

rₛ = peak response of ondansetron from the Standard solution

Cₛ = concentration of USP Ondansetron Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = concentration of Ondansetron Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

Table 3

▲ (USP 1-Aug-2024)

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I, Method Ia: 9.0%–10.5%

Add the following:

▲• Bacterial Endotoxins Test 〈85〉: Where the label states that Ondansetron Hydrochloride must be subjected to further processing during the preparation of injectable dosage forms, the level of bacterial endotoxins are such that the requirement under the relevant dosage form monograph(s) in which Ondansetron Hydrochloride is used can be met.▲ (USP 1-Aug-2024)

Add the following:

▲• Microbial Enumeration Tests 〈61〉: The total aerobic microbial count does not exceed 10² cfu/g and the total combined molds and yeast count does not exceed 50 cfu/g.▲ (USP 1-Aug-2024)

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers. Store at 25°, excursions permitted between 15° and 30°.

Add the following:

▲• Labeling: Where it is intended for use in preparing injectable dosage forms, the label states that it is sterile or must be subjected to further processing during the preparation of injectable dosage forms.▲ (USP 1-Aug-2024)

Change to read:

USP Reference Standards 〈11〉

▲ USP Imidazole RS

1H-Imidazole.

C₃H₄N₂ 68.08▲ (USP 1-Aug-2024)

USP Ondansetron Hydrochloride RS

▲▲ (USP 1-Aug-2024)

USP Ondansetron Related Compound D RS

9-Methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one.

▲C₁₄H₁₃NO 211.26

USP Ondansetron Related Compound G

3-[(1H-Imidazole-1-yl)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one.

C₁₇H₁₇N₃O 279.34▲ (USP 1-Aug-2024)

USP Ondansetron Resolution Mixture RS

▲Contains a mixture of the following 3 compounds:

Ondansetron hydrochloride.

Ondansetron related compound A;

3-[(Dimethylamino)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride.

C₁₆H₂₀N₂O · HCl 292.81

Methylene bisondansetron;

6,6'-Methylenebis{9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one}.

C₃₇H₃₈N₆O₂ 598.75▲ (USP 1-Aug-2024)