Granisetron 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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C₁₈H₂₄N₄O · HCl 348.87

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

1-Methyl-N-(9-methyl-endo-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide monohydrochloride CAS RN®: 107007-99-8; UNII:  318F6L70J8.

1 DEFINITION

Granisetron Hydrochloride contains NLT 97.0% and NMT 102.0% of granisetron hydrochloride (C₁₈H₂₄N₄O · HCl), calculated on the dried basis. 

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M

B. Identification Tests—General 〈191〉, Chemical Identification Tests, Chloride: Meets the requirements

3 ASSAY

Procedure

Mobile phase: Acetonitrile, water, phosphoric acid, and hexylamine (200: 800: 1.6: 1.0). Adjust with triethylamine to a pH of 7.5 ± 0.05 (about 4 mL is needed). Make adjustments if necessary. (See Chromatography 〈621〉, System Suitability.)

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

System suitability solution: Transfer 2 mL of Standard solution 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. Sample solution: 1.0 mg/mL of Granisetron Hydrochloride 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: Standard solution and System suitability solution

Suitability requirements

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

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

Relative standard deviation: NMT 2.0%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of granisetron hydrochloride (C₁₈H₂₄N₄O · HCl) in the portion of Granisetron Hydrochloride taken: 

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

r_U = peak response of granisetron from the Sample solution

r_S = peak response of granisetron from the Standard solution

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

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

Acceptance criteria: 97.0%–102.0% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

4.1 Organic Impurities

[Note—Protect all solutions containing Granisetron Hydrochloride from light.]

Mobile phase, System suitability solution, and Sample solution: Prepare as directed in the Assay.

Peak identification solution: 0.01 mg/mL of USP Granisetron Related Compound A RS and 0.005 mg/mL of USP Granisetron Related Compound B RS in Mobile phase

Standard solution: 0.005 mg/mL of USP Granisetron Hydrochloride RS in Mobile phase

Chromatographic system: Proceed as directed in the Assay, except for the Run time.

Run time: NLT 2 times the retention time of granisetron

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

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

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

Relative standard deviation: NMT 10%, Standard solution

Analysis

Samples: Peak identification solution, Standard solution, and Sample solution

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

Result = (r_U /r_S ) × (C_S /C_U) × (1/F) × 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 Hydrochloride RS in the Standard solution (mg/mL)

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

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. Discard any peaks observed in the blank. The reporting threshold is 0.05%.

Table 1

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

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

4.2 Limit of Granisetron Related Compound E

Diluent: Acetonitrile and water (80:20)

Standard solution: 0.25 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 Hydrochloride in Diluent

4.2.1 Chromatographic system

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

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 2 µL

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

4.2.2 Analysis

Samples: Standard solution and Sample solution

Proceed as directed in Chromatography 〈621〉, General Procedures, Thin-Layer Chromatography 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 (0.5%).

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° for 4 h.

Acceptance criteria: NMT 0.5%

pH 〈791〉

Sample solution: 10 mg/mL in carbon dioxide-free water

Acceptance criteria: 4.0–6.5

6 ADDITIONAL REQUIREMENTS

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

USP Reference Standards 〈11〉

USP Granisetron Hydrochloride RS

USP Granisetron Related Compound A RS

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

USP Granisetron Related Compound B RS

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

USP Granisetron Related Compound E RS

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