Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n
Action and use<\/strong><\/p>\n Tyrosine kinase inhibitor; treatment of metastatic colorectal cancer and unresectable or metastatic gastrointestinal stromal tumours.<\/p>\n Preparation <\/strong><\/p>\n Regorafenib Tablets<\/p>\n 4-[4-[[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl]amino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate.<\/p>\n Content<\/strong><\/p>\n 98.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n White or almost white or pinkish or brownish powder.<\/p>\n Practically insoluble in water, sparingly soluble in acetone, slightly soluble in ethanol (96 per cent) and in methanol, practically insoluble in heptane.<\/p>\n It shows polymorphism (5.9).<\/p>\n A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n Comparison\u00a0 regorafenib monohydrate CRS.<\/p>\n If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in acetone R, evaporate to dryness and record new spectra using the residues.<\/p>\n B. Water (see Tests).<\/p>\n Liquid chromatography (2.2.29). Carry out the test protected from light and store the solutions at 2-8 \u00b0C.<\/p>\n Test solution Dissolve 0.250 g of the substance to be examined in tetrahydrofuran R and dilute to 5.0 mL with the same solvent.<\/p>\n Reference solution Dissolve 5.0 mg of regorafenib impurity A CRS in tetrahydrofuran R and dilute to 50.0 mL with the same solvent. Dilute 2.5 mL of the solution to 50.0 mL with tetrahydrofuran R.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.15 m, \u00d8 = 3.0 mm;<\/p>\n \u2014 stationary phase: end-capped ethylene-bridged polar-embedded octadecylsilyl silica gel for chromatography (hybrid material) R (3.5 \u00b5m);<\/p>\n \u2014 temperature: 50 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: mix 8 volumes of acetonitrile for chromatography R and 92 volumes of a solution containing 0.5 g\/L of dipotassium hydrogen phosphate R and 1.5 g\/L of potassium dihydrogen phosphate R;<\/p>\n \u2014 mobile phase B: acetonitrile for chromatography R;<\/p>\n Flow rate\u00a0 1.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 228 nm.<\/p>\n Autosampler\u00a0 Set at 8 \u00b0C.<\/p>\n Injection\u00a0 3.0 \u00b5L.<\/p>\n Relative retention\u00a0 With reference to regorafenib (retention time = about 14 min): impurity A = about 0.6.<\/p>\n System suitability\u00a0 Reference solution:<\/p>\n \u2014 repeatability: maximum relative standard deviation of 10.0 per cent determined on 6 injections.<\/p>\n Calculation of content:<\/p>\n \u2014 for impurity A, use the concentration of impurity A in the reference solution.<\/p>\n Limit:<\/p>\n \u2014 impurity A: maximum 100 ppm.<\/p>\n Liquid chromatography (2.2.29). Carry out the test protected from light and store the solutions at 2-8 \u00b0C.<\/p>\n Test solution (a) Dissolve 30.0 mg of the substance to be examined in methanol R and dilute to 20.0 mL with the same solvent.<\/p>\n Test solution (b)\u00a0 Dilute 15.0 mL of test solution (a) to 50.0 mL with methanol R.<\/p>\n Reference solution (a) Dissolve 30.0 mg of regorafenib monohydrate CRS in methanol R and dilute to 20.0 mL with the same solvent. Dilute 15.0 mL of the solution to 50.0 mL with methanol R.<\/p>\n Reference solution (b)\u00a0 Dilute 1.0 mL of test solution (a) to 100.0 mL with methanol R. Dilute 1.0 mL of this solution to 10.0 mL with methanol R.<\/p>\n Reference solution (c)\u00a0 Dissolve 2 mg of sorafenib CRS in methanol R and dilute to 50 mL with the same solvent. Dilute 0.2 mL of the solution to 2 mL with test solution (a).<\/p>\n Reference solution (d) Dissolve 3 mg of regorafenib impurity C CRS in methanol R and dilute to 100 mL with the same solvent.<\/p>\n Reference solution (e) Dissolve 3 mg of regorafenib impurity D CRS in dimethyl sulfoxide R and dilute to 100 mL with the same solvent.<\/p>\n Reference solution (f)\u00a0 Mix 1 mL of reference solution (d) and 1 mL of reference solution (e) and dilute to 20 mL with methanol R. Column:<\/p>\n \u2014 size: l = 0.15 m, \u00d8 = 2.1 mm;<\/p>\n \u2014 stationary phase: end-capped ethylene-bridged phenylsilyl silica gel for chromatography (hybrid material) R (3.5 \u00b5m);<\/p>\n \u2014 temperature: 63 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: acetonitrile for chromatography R, 0.1 per cent V\/V solution of trifluoroacetic acid R (3:97 V\/V);<\/p>\n \u2014 mobile phase B: acetonitrile for chromatography R;<\/p>\n Flow rate\u00a0 0.9 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 232 nm.<\/p>\n Autosampler\u00a0 Set at 8 \u00b0C.<\/p>\n Injection\u00a0 5 \u00b5L of test solution (a) and reference solutions (b), (c) and (f).<\/p>\n Identification of peaks Use the chromatogram obtained with reference solution (f) to identify the peaks due to impurities C and D; use the chromatogram obtained with reference solution (c) to identify the peak due to sorafenib.<\/p>\n Relative retention With reference to regorafenib (retention time = about 25 min): impurity C = about 0.4; impurity D = about 0.8; sorafenib = about 0.95.<\/p>\n System suitability\u00a0 Reference solution (c):<\/p>\n \u2014 resolution: minimum 3.0 between the peaks due to sorafenib and regorafenib.<\/p>\n Calculation of percentage contents:<\/p>\n \u2014 correction factors: multiply the peak areas of the following impurities by the corresponding correction factor: impurity C = 0.5; impurity D = 0.6;<\/p>\n \u2014 for each impurity, use the concentration of regorafenib monohydrate in reference solution (b).<\/p>\n Limits:<\/p>\n \u2014 impurity D: maximum 0.2 per cent;<\/p>\n \u2014 impurity C: maximum 0.15 per cent;<\/p>\n \u2014 unspecified impurities: for each impurity, maximum 0.10 per cent;<\/p>\n \u2014 total: maximum 0.5 per cent;<\/p>\n \u2014 reporting threshold: 0.05 per cent.<\/p>\n Water (2.5.32)<\/strong><\/p>\n 3.2 per cent to 4.0 per cent, determined on 50.0 mg using the evaporation technique at 150 \u00b0C.<\/p>\n Sulfated ash (2.4.14)<\/strong><\/p>\n Maximum 0.1 per cent, determined on 1.0 g in a platinum crucible.<\/p>\n Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.<\/p>\n Injection\u00a0 Test solution (b) and reference solution (a).<\/p>\n Calculate the percentage content of C21<\/sub>H15<\/sub>ClF4<\/sub>N4<\/sub>O3<\/sub> taking into account the assigned content of regorafenib monohydrate CRS.<\/p>\n Specified impurities\u00a0 A, C, D.<\/em><\/p>\n 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) B, E.<\/em><\/p>\n A. 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide,<\/p>\n B. 4-(4-acetamido-3-fluorophenoxy)-N-methylpyridine-2-carboxamide,<\/p>\n C. 4-[3-fluoro-4-[[2-(methylcarbamoyl)pyridin-4-yl]amino]phenoxy]-N-methylpyridine-2-carboxamide,<\/p>\n D. 33,72-difluoro-N,N\u2032-dimethyl-5-oxo-2,8-dioxa-4,6-diaza-1(4),9(4)-dipyridina-3(1,4),7(1,4)-dibenzenanonaphane-12,92- dicarboxamide,<\/p>\n E. 94-chloro-34-[[[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl]amino]-53-fluoro-N-methyl-7-oxo-93-(trifluoromethyl)-2,4-\u00a0 dioxa-6,8-diaza-1(4)-pyridina-3(1,3),5(1,4),9(1)-tribenzenanonaphane-12-carboxamide.<\/p>\n","protected":false},"excerpt":{"rendered":" Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Tyrosine kinase inhibitor; treatment of metastatic colorectal cancer and unresectable or metastatic gastrointestinal stromal tumours. Preparation Regorafenib Tablets DEFINITION 4-[4-[[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl]amino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Content 98.0 per cent to 102.0 per cent (anhydrous substance). CHARACTERS Appearance White or almost white or pinkish or brownish powder. Solubility Practically insoluble…<\/p>\n","protected":false},"author":5,"featured_media":29452,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-29450","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicinal-substances"],"acf":[],"_links":{"self":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29450","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=29450"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29450\/revisions"}],"predecessor-version":[{"id":29474,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29450\/revisions\/29474"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/29452"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=29450"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=29450"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=29450"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}DEFINITION<\/h2>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
Solubility<\/h3>\n
IDENTIFICATION<\/h2>\n
TESTS<\/h2>\n
Impurity A<\/h3>\n
\n\n
\n Time (min)<\/strong><\/td>\n Mobile phase A (per cent V\/V)<\/strong><\/td>\n Mobile phase B (per cent V\/V)<\/strong><\/td>\n<\/tr>\n \n 0 – 2<\/td>\n 100<\/td>\n 0<\/td>\n<\/tr>\n \n 2 – 17<\/td>\n 100 \u2192 22<\/td>\n 0 \u2192 78<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n Related substances<\/h3>\n
\n\n
\n Time (min)<\/strong><\/td>\n Mobile phase A (per cent V\/V)<\/strong><\/td>\n Mobile phase B (per cent V\/V)<\/strong><\/td>\n<\/tr>\n \n 0 – 2<\/td>\n 100<\/td>\n 0<\/td>\n<\/tr>\n \n 2 – 15<\/td>\n 100 \u2192 78<\/td>\n 0 \u2192 22<\/td>\n<\/tr>\n \n 15 – 25<\/td>\n 78 \u2192 60<\/td>\n 22 \u2192 40<\/td>\n<\/tr>\n \n 25 – 33<\/td>\n 60 \u2192 36<\/td>\n 40 \u2192 64<\/td>\n<\/tr>\n \n 33 – 37<\/td>\n 36<\/td>\n 64<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n ASSAY<\/h2>\n
IMPURITIES<\/h2>\n