granisetron-6.0

EUROPEAN PHARMACOPOEIA 6.0 Granisetron hydrochloride 01/2008:1695 corrected 6.0 GRANISETRON HYDROCHLORIDE Granisetroni hydrochloridum C18H25ClN4O Mr 348.9 [107007-99-8] DEFINITION 1-Methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]- 1H-indazole-3-carboxamide hydrochloride. Content : 97.0 per cent to 102.0 per cent (dried substance). CHARACTERS Appearance : white or almost white powder. Solubility : freely soluble in water, sparingly soluble in methylene chloride, slightly soluble in methanol. IDENTIFICATION A. Infrared absorption spectrophotometry (2.2.24). Comparison : granisetron hydrochloride CRS. B. It gives reaction (a) of chlorides (2.3.1). TESTS Solution S. Dissolve 0.2 g in carbon dioxide-free water R and dilute to 20 ml with the same solvent. Appearance of solution. Solution S is clear (2.2.1) and colourless (2.2.2, Method II). pH (2.2.3) : 4.0 to 6.5 for solution S. Impurity E. Thin-layer chromatography (2.2.27). Test solution. Dissolve 0.25 g of the substance to be examined in a mixture of 20 volumes of water R and 80 volumes of acetonitrile R and dilute to 5 ml with the same mixture of solvents. Reference solution. Dissolve 5 mg of granisetron impurity E CRS in a mixture of 20 volumes of water R and 80 volumes of acetonitrile R and dilute to 20 ml with the same mixture of solvents. Plate : TLC silica gel F254 plate R. Mobile phase : concentrated ammonia R, 2-propanol R, ethyl acetate R (6.5:30:50 V/V/V). Application : 2 µl. Development : over half of the plate. Drying : in air. Detection : expose to iodine vapour for 30 min. Limit : — impurity E : any spot due to impurity E is not more intense than the principal spot in the chromatogram obtained with the reference solution (0.5 per cent). Related substances. Liquid chromatography (2.2.29). Carry out the test protected from light. Test solution. Dissolve 50.0 mg of the substance to be examined in the mobile phase and dilute to 50.0 ml with the mobile phase. 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 mobile phase. 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 h or under a UV lamp for 16 h (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). Dissolve 50.0 mg of granisetron hydrochloride CRS in the mobile phase and dilute to 50.0 ml with the mobile phase. Reference solution (d). Dissolve the contents of a vial of granisetron impurity A CRS in 1 ml of the mobile phase. Reference solution (e). Dissolve the contents of a vial of granisetron impurity B CRS in 1 ml of the mobile phase. Column : — size : l = 0.25 m, Ø = 4.6 mm, — stationary phase : spherical base-deactivated end-capped octadecylsilyl silica gel for chromatography R (5 µm), — temperature : 40 °C. Mobile phase : dilute 1.6 ml of phosphoric acid R to 800 ml with water R, add 200 ml of acetonitrile R and mix. Add 1.0 ml of hexylamine R and mix. Adjust to pH 7.5 ± 0.05 with freshly distilled triethylamine R (about 4 ml). Flow rate : 1.5 ml/min. Detection : spectrophotometer at 305 nm. Injection : 10 µl of the test solution and reference solutions (a), (b), (d) and (e). Run time : twice the retention time of granisetron. Relative retention with reference to granisetron (retention time = about 7 min) : impurity D = about 0.4 ; impurity B = about 0.5 ; impurity A = about 0.7 ; impurity C = about 0.8. System suitability : — resolution : minimum 3.5 between the peaks due to impurity C and granisetron in the chromatogram obtained with reference solution (b), — symmetry factor : maximum 2.0 for the peak due to granisetron. Limits : — correction factor : for the calculation of content, multiply the peak area of impurity B by 1.7, — impurity A : not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent), — impurity B : not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent), — impurity C : not more than 0.4 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent), — impurity D : not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent), — any other impurity : for each impurity, not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent), — total : not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent), General Notices (1) apply to all monographs and other texts 2009 Greater celandine EUROPEAN PHARMACOPOEIA 6.0 — disregard limit : 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent) ; disregard any peak due to the blank. Loss on drying (2.2.32) : maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 4 h. Sulphated ash (2.4.14) : maximum 0.1 per cent, determined on 1.0 g. ASSAY Liquid chromatography (2.2.29) as described in the test for related substances with the following modification. Injection : test solution and reference solution (c). Calculate the percentage content of C18H25ClN4O using the declared content of granisetron hydrochloride CRS. IMPURITIES Specified impurities : A, B, C, D, E. Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use) : F, G, H, I. A. 2-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3- yl]-2H-indazole-3-carboxamide, B. R = H, R′ = CH3: N-[(1R,3r,5S)-9-methyl-9- azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide, C. R = CH3, R′ = H: N-[(1R,3r,5S)-9-azabicyclo[3.3.1]non-3- yl]-1-methyl-1H-indazole-3-carboxamide, D. R = CH3 : 1-methyl-1H-indazole-3-carboxylic acid, H. R = H: 1H-indazole-3-carboxylic acid, E. (1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine, F. 1-methyl-N-[(1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]non-3- yl]-1H-indazole-3-carboxamide (exo-granisetron), G. 2-methyl-2H-indazole-3-carboxylic acid, I. 1-methyl-1H-indazole-3-carboxylic anhydride. 01/2008:1861 corrected 6.0 GREATER CELANDINE Chelidonii herba DEFINITION Dried, whole or cut aerial parts of Chelidonium majus L. collected during flowering. Content : minimum 0.6 per cent of total alkaloids, expressed as chelidonine (C20H19NO5 ; Mr 353.4) (dried drug). IDENTIFICATION A. The stems are rounded, ribbed, yellowish or greenish-brown, somewhat pubescent, about 3-7 mm in diameter, hollow and mostly collapsed. The leaves are thin, irregularly pinnate, the leaflets ovate to oblong with coarsely dentate margins, the terminal leaflet often three-lobed ; the adaxial surface is bluish-green and glabrous, the abaxial surface paler and pubescent, especially on the veins. The flowers have 2 deeply concavo-convex sepals, readily removed, and 4 yellow, broadly ovate, spreading petals about 8-10 mm long; the stamens are numerous, yellow, and a short style arises from a superior ovary ; long, capsular, immature fruits are rarely present. B. Reduce to a powder (355) (2.9.12). The powder is dark greyish-green or brownish-green. Examine under a microscope using chloral hydrate solution R. The powder shows the following diagnostic characters : numerous fragments of leaves in surface view, the epidermal cells with sinuous walls ; anomocytic stomata (2.8.3) occur on the abaxial surface only ; covering trichomes long, uniseriate, with thin walls and usually fragmented ; vascular tissue from the leaves and stems with groups of fibres, pitted and spirally thickened vessels and associated latex tubes with yellowish-brown contents ; occasional fragments of the corolla with thin-walled, partly papillose cells containing numerous pale yellow droplets of oil ; spherical pollen grains about 30-40 µm in diameter with 3 pores and a finely pitted exine. 2010 See the information section on general monographs (cover pages)