Granisetron

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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C₁₈H₂₄N₄O           312.41

1H-Indazole-3-carboxamide, 1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]-non-3-yl)-, endo-;

1-Methyl-N-(9-methyl-endo-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide CAS RN®: 109889-09-0.

1 DEFINITION

Granisetron contains NLT 98.0% and NMT 102.0% of granisetron (C₁₈H₂₄N₄O), calculated on the dried basis. 

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K _{(CN 1-May-2020)}

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

3 ASSAY

Procedure

Mobile phase: Dilute 1.6 mL of phosphoric acid with water to 800 mL, and then add 200 mL of acetonitrile. Add 1.0 mL of hexylamine. Adjust with triethylamine to a pH of 7.5 ± 0.05 (about 4 mL is needed).

System suitability solution: Transfer 2 mL of a solution containing about 1.0 mg/mL of granisetron in Mobile phase to a colorless glass vial, stopper it, and either expose the solution to sunlight for 4 h or place it under a UV lamp for 16 h (granisetron undergoes partial degradation to granisetron related compound C). A degradation of at least about 0.3% of granisetron to granisetron related compound C must be obtained, as shown by the appearance of a corresponding peak in the chromatogram. If it is not obtained, again expose the solution to sunlight or place it under a UV lamp.

Standard solution: 1.0 mg/mL of USP Granisetron RS in Mobile phase

Sample solution: 1.0 mg/mL of Granisetron in Mobile phase

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 305 nm

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

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 10 µL

3.2 System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 3.5 between granisetron and granisetron related compound C, System suitability solution

Tailing factor: NMT 2.0 for the granisetron peak, System suitability solution

Relative standard deviation: NMT 0.73%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of granisetron (C₁₈H₂₄N₄O) in the portion of Granisetron taken:

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

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

C_U = concentration of Granisetron in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

4.1 Limit of Granisetron Related Compound E

Diluent: Acetonitrile and water (80:20)

Standard solution: 0.075 mg/mL of USP Granisetron Related Compound E RS in Diluent

[Note—USP Granisetron Related Compound E RS is the acetate salt of (1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine. Use the correction factor stated on the label of the USP Reference Standard to calculate the concentration, as appropriate.] Sample solution: 50 mg/mL of Granisetron in Diluent

4.1.1 Chromatographic system

(See Chromatography 〈621〉, General Procedures, Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 10 µL

Developing solvent system: Ethyl acetate, isopropyl alcohol, and ammonium hydroxide (50:30:6.5)

4.1.2 Analysis

Samples: Standard solution and Sample solution

Proceed as directed in the chapter and develop the chromatogram until the solvent front has moved about half of the length of the plate. Dry the plate in air, and expose it to iodine vapor for 30 min.

Acceptance criteria: Any spot corresponding to granisetron related compound E from the Sample solution is not more intense than the corresponding spot from the Standard solution (NMT 0.15%).

4.2 Organic Impurities

[Note—Protect all solutions containing granisetron from light.]

Mobile phase, System suitability solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 0.001 mg/mL of USP Granisetron RS in Mobile phase

Sample solution: 1.0 mg/mL of Granisetron in Mobile phase. Inject this solution within 4 h of preparation.

4.2.1 System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 3.5 between granisetron and granisetron related compound C, System suitability solution

Tailing factor: NMT 2.0 for the granisetron peak, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

4.2.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Granisetron taken:

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of granisetron from the Standard solution

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

C_U = concentration of Granisetron in the Sample solution (mg/mL)

Acceptance criteria: See Table 1. The reporting threshold for impurities is 0.05%.

Table 1

^a 1-Methyl-1H-indazole-3-carboxylic acid. 

^b N-[(1R,3r,5S)-9-Methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide.

^c 2-Methyl-N-[1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-2H-indazole-3-carboxamide.

^d N-[(1R,3r,5S)-9-Azabicyclo[3.3.1]non-3-yl]-1-methyl-1H-indazole-3-carboxamide.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 4 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, protected from light. Store at room temperature.

USP Reference Standards 〈11〉

USP Granisetron RS

USP Granisetron Related Compound E RS

Granisetron amine acetate;

(1R,3r,5S)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine acetate.

C₉H₁₈N₂ · C₂H₄O₂                   214.31