भारतीय भेषज संहिता आयोग
Granisetron Hydrochloride
C18H25ClN4O Mol. Wt. 348.9
Granisetron Hydrochloride is 1-Methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide hydrochloride.
Granisetron Hydrochloride contains not less than 97.0 per cent and not more than 102.0 per cent of C18H25ClN4O, calculated on the dried basis.
Category. Serotonin 5HT3 receptor antagonist; treatment of nausea and vomiting,
Dose. 1 mg twice a day.
Description. A white or almost white powder.
Identification
- Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained withgranisetron hydrochloride RSor with the reference spectrum of granisetron hydrochloride.
- In the assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the reference solution (c).
- A 1.0 per cent w/v solution gives the reaction (A) of chlorides (2.3.1).
Tests
Appearance of solution. A 1.0 per cent w/v solution (Solution A) is clear and colourless (2.4.1).
pH (2.4.24). 4.0 to 6.5, determined in solution A.
Impurity E. Determine by thin layer chromatography (2.4.17), coating the plate with silica gel GF254.
Solvent mixture. A mixture of 20 volumes of water and 80 volumes of acetonitrile.
Mobile phase. A mixture of 6.5 volumes of ammonia, 30 volumes of 2-propanol and
50 volumes of ethyl acetate.
Test solution. Dissolve 0.5 g of the substance under examination in 10.0 ml of solvent mixture.
Reference solution. A 0.025 per cent w/v solution of granisetron impurity E RS in solvent mixture .
Apply to the plate 2 µl of each solution. After development, dry the plate in air and expose it to iodine vapours for 30 minutes. Any secondary spot, corresponding to the spot obtained with reference solution, in the chromatogram obtained with the test solution is not more intense than the spot in the chromatogram obtained with reference solution (0.5 per cent).
Related substances. Determine by liquid chromatography (2.4.14).
Test solution. Dissolve 50 mg of the substance under examination in the mobile phase and dilute to 50.0 ml with the same solvent.
Reference solution (a). Dilute 1.0 ml of the test solution to 50.0 ml with the mobile phase. Dilute 5.0 ml of this solution to 20.0 ml with the same solvent.
Reference solution (b). Transfer 2 ml of the test solution to a colourless glass vial, stopper and expose the solution either to sunlight for 4 hour or under a UV lamp for 16 hour (partial degradation of granisetron to impurity C). A degradation of at least about 0.3 per cent of granisetron to impurity C must be obtained as shown by appearance of a corresponding peak in the chromatogram. If not, expose the solution once again to sunlight or under a UV lamp.
Reference solution (c). A 0.1 per cent w/v solution of granisetron hydrochloride RS in the mobile.
Reference solution (d). A 0.1 per cent w/v solution of granisetron impurity A RS in the mobile phase.
Reference solution (e). A 0.1 per cent w/v solution of granisetron impurity B RS in the mobile phase.
Chromatographic system
– a stainless steel column 25 cm × 4.6 mm, base deactivated end-capped packed with octadecylsilane bonded to porous silica (5 µm),
– column temperature: 40°,
– mobile phase: a mixture of 80 volumes of water, 20 volumes of acetonitrile, 0.1 volume of hexylamine and 0.16 volume of orthophosphoric acid. Adjusted to pH 7.5 ± 0.05 with freshly distilled triethylamine,
– flow rate: 1.5 ml per minute,
– spectrophotometer set at 305 nm,
– injection volume: 10 µl.
Name Relative Correction
retention time factor
Granisetron impurity A1 0.7 ---
Granisetron impurity B2 0.5 1.7
Granisetron impurity C3 0.8 ---
Granisetron impurity D4 0.4 ---
Granisetron (Retention time:
about 7.0 minutes) 1.0 ---
1 2-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-2H-indazole-3-carboxamide,
2 N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nons-3-yl]-1H-indazole-3-carboxamide,
3 N-[(1R,3r,5S)-9-azabicyclo[3.3.1]non-3-yl]-1-methyl-1H-indazole-3-carboxamide,
4 1-methyl-1H-indazole-3-carboxylic acid,
Inject reference solutions (a), (b), (d), (e) and the test solution.
Run the chromatogram twice the retention time of peak due to granisetron.
Inject reference solution (b). The test is not valid unless the resolution between the peaks corresponding to impurity C and granisetron is not less than 3.5 and the tailing factor is not more than 2.0
Inject reference solution (a) and the test solution. In the chromatogram obtained with the test solution, the area of peak corresponding to impurity B is not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent). The area of peak corresponding to impurity C is not more than 0.4 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent). The area of peak corresponding to impurity A is not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent). The area of peak corresponding to impurity D is not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent). The area of any secondary peak is not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent). The sum of areas of all the secondary peaks is not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a)
(1.0 per cent). Ignore any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).
Sulphated ash (2.3.18). Not more than 0.1 per cent.
Loss on drying (2.4.19). Not more than 0.5 per cent, determined on 1.0 g by drying in an oven at 105° for 4 hours.
Assay. Determine by liquid chromatography (2.4.14) as described under related substances with the following modification.
Inject the test solution and reference solution (c).
Calculate the content of C18H25ClN4O.
Storage. Store protected from light and moisture.
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Solubility : Freely soluble in water, sparingly soluble in methylene chloride, slightly soluble in methanol.
