Granisetron Hydrochloride
(gra nis' e tron hye'' droe klor' ide).
+'&img=../../images/v35300/cas-107007-99-8.gif&casNumber=107007-99-8&usp=35&nf=30&chemicalStructureImage=true&ID='+parent.myID,600,500);)
348.871H-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
[107007-99-8].» Granisetron Hydrochloride contains not less than 97.0 percent and not more than 102.0 percent of C18H24N4O·HCl, calculated on the dried basis.
Packaging and storage—
Preserve in well-closed containers, protected from light. Store at room temperature.
USP Reference standards 
11
—
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).
(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,5)-9-Methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide).
(N-[(1R,3r,5)-9-Methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide).
USP Granisetron Related Compound E RS
((1R,3rS,5S)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine, acetate salt).
((1R,3rS,5S)-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine, acetate salt).
Identification—
B:
It meets the requirements of the test for Chloride 191.
191.
pH 791:
between 4.0 and 6.5, in a solution in carbon dioxide-free water, containing 10 mg per mL.
791:
between 4.0 and 6.5, in a solution in carbon dioxide-free water, containing 10 mg per mL.
Loss on drying 731—
Dry it at 105
for 4 hours: it loses not more than 0.5% of its weight.
731—
Dry it at 105 for 4 hours: it loses not more than 0.5% of its weight.
Residue on ignition 281:
not more than 0.1%.
281:
not more than 0.1%.
Heavy metals, Method II 231:
not more than 20 ppm.
231:
not more than 20 ppm.
Limit of granisetron related compound E—
Adsorbent:
0.25-mm layer of chromatographic silica gel mixture.
Diluent:
a mixture of acetonitrile and water (80:20).
Test solution—
Transfer 250 mg of Granisetron Hydrochloride to a 5-mL volumetric flask, and dissolve in and dilute with Diluent to volume.
Standard solution—
Dissolve an accurately weighed quantity of USP Granisetron Related Compound E RS in Diluent to obtain a solution containing 0.25 mg per mL. [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. ]
Application volume:
2 µL.
Developing solvent system—
A mixture of ethyl acetate, isopropyl alcohol, and ammonium hydroxide (50:30:6.5).
Procedure—
Proceed as directed for Thin-Layer Chromatography under Chromatography 621, 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 minutes. Any spot corresponding to granisetron related compound E obtained from the Test solution is not more intense than the corresponding spot obtained from the Standard solution (0.5%).
621, 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 minutes. Any spot corresponding to granisetron related compound E obtained from the Test solution is not more intense than the corresponding spot obtained from the Standard solution (0.5%).
Related compounds—
[note—Protect all solutions containing granisetron hydrochloride from light. ]
Mobile phase and System suitability solution—
Proceed as directed in the Assay.
Standard solution—
Dissolve an accurately weighed quantity of USP Granisetron Hydrochloride RS in Mobile phase to obtain a solution having a known concentration of about 0.005 mg per mL.
Identification solution—
Prepare a solution in Mobile phase containing 0.01 mg per mL of USP Granisetron Related Compound A RS and 0.005 mg per mL of USP Granisetron Related Compound B RS.
Test solution—
Use the Assay preparation, prepared as directed in the Assay.
Chromatographic system
(see Chromatography 621)—Prepare as directed in the Assay. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between granisetron related compound C and granisetron is not less than 3.5; and the tailing factor for the granisetron peak is not more than 2.0. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 10%.
621)—Prepare as directed in the Assay. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between granisetron related compound C and granisetron is not less than 3.5; and the tailing factor for the granisetron peak is not more than 2.0. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 10%.
Procedure—
Separately inject equal volumes (about 10 µL) of the Standard solution, the Identification solution, and the Test solution into the chromatograph, record the chromatograms for about two times the retention time of granisetron, identify the peaks on the basis of their relative retention times as given in Table 1, and measure the peak responses. Calculate the percentage of each impurity in the portion of Granisetron Hydrochloride taken by the formula:
100(1 / F)(CS / CT)(rU / rS)
in which F is the relative response factor given in Table 1; CS and CT are the concentrations, in mg per mL, of granisetron hydrochloride in the Standard solution and the Test solution, respectively; rU is the peak response for each impurity obtained from the Test solution; and rS is the peak response for granisetron obtained from the Standard solution: in addition to not exceeding the limits in Table 1, not more than 1.0% of total impurities is found. Disregard any peak observed in the blank. The reporting level for impurities is 0.05%.
Table 1
| Name | Relative Retention Time |
Relative Response Factor (F) |
Limit (%) |
|---|---|---|---|
| Granisetron related compound D1 | 0.4 | 1.0 | 0.1 |
| Granisetron related compound B2 | 0.5 | 0.59 | 0.5 |
| Granisetron related compound A3 | 0.7 | 1.0 | 1.0 |
| Granisetron related compound C4 | 0.8 | 1.0 | 0.2 |
| Granisetron | 1.0 | n/a | n/a |
| Any other individual impurity | n/a | 1.0 | 0.1 |
|
1
1-Methyl-1H-indazole-3-carboxylic acid.
2
N-[(1R,3r,5S)-9-Methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide.
3
2-Methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-2H-indazole-3-carboxamide.
4
N-[(1R,3r,5S)-9-Azabicyclo[3.3.1]non-3-yl]-1-methyl-1H-indazole-3-carboxamide.
|
|||
Assay—
Mobile phase—
Dilute 1.6 mL of phosphoric acid with water to 800 mL, add 200 mL of acetonitrile, and mix. Add 1.0 mL of hexylamine, and mix. Adjust with triethylamine to a pH of 7.5 ± 0.05 (about 4 mL is needed). Make adjustments if necessary (see System Suitability under Chromatography 621).
621).
Standard preparation—
Dissolve an accurately weighed quantity of USP Granisetron Hydrochloride RS in Mobile phase to obtain a solution having a known concentration of about 1.0 mg per mL.
System suitability solution—
Transfer 2 mL of a solution in Mobile phase containing about 1.0 mg of Granisetron Hydrochloride per mL to a colorless glass vial, stopper it, and either expose the solution to sunlight for 4 hours or place it under a UV lamp for 16 hours (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.
Assay preparation—
Transfer about 50 mg of Granisetron Hydrochloride, accurately weighed, to a 50-mL volumetric flask, dissolve in and dilute with Mobile phase to volume, and mix.
Chromatographic system
(see Chromatography 621)—The liquid chromatograph is equipped with a 305-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The column temperature is maintained at 40. The flow rate is about 1.5 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between granisetron related compound C and granisetron is not less than 3.5; and the tailing factor for the granisetron peak is not more than 2.0. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 2.0%.
621)—The liquid chromatograph is equipped with a 305-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The column temperature is maintained at 40. The flow rate is about 1.5 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between granisetron related compound C and granisetron is not less than 3.5; and the tailing factor for the granisetron peak is not more than 2.0. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the percentage of C18H24N4O·HCl in the portion of Granisetron Hydrochloride taken by the formula:
100(CS / CU)(rU / rS)
in which CS and CU are the concentrations, in mg per mL, of granisetron hydrochloride in the Standard preparation and the Assay preparation, respectively; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Elena Gonikberg, Ph.D.
Principal Scientific Liaison 1-301-816-8251 |
(SM32010) Monographs - Small Molecules 3 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 3372
Pharmacopeial Forum: Volume No. 33(6) Page 1176