Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n
Action and use<\/strong><\/p>\n Beta-adrenoceptor antagonist. Ph Eur<\/p>\n (1RS)-1-[(2RS)-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-[[(2RS)-2-[(2SR)-6-fluoro-3,4-dihydro-2H-1-\u00a0 benzopyran-2-yl]-2-hydroxyethyl]amino]ethan-1-ol hydrochloride.<\/p>\n Content<\/strong><\/p>\n 98.0 per cent to 102.0 per cent (dried substance).<\/p>\n White or almost white crystalline powder.<\/p>\n Very slightly soluble in water, sparingly soluble in methanol, very slightly soluble in heptane.<\/p>\n A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n Comparison\u00a0 nebivolol hydrochloride CRS.<\/em><\/p>\n B. Dissolve 20 mg in 20 mL of methanol R and add 1 mL of silver nitrate solution R1. Shake and allow to stand. A curdled, white precipitate is formed. Remove the supernatant and suspend the precipitate in 5 mL dilute nitric acid R. The precipitate does not dissolve. Add 20 mL of ammonia R and shake well. The precipitate dissolves easily with the possible exception of a few large particles which dissolve slowly.<\/p>\n Liquid chromatography (2.2.29).<\/p>\n Test solution\u00a0 Dissolve 20.0 mg of the substance to be examined in methanol R and dilute to 5.0 mL with the same solvent.<\/p>\n Reference solution (a)\u00a0 Dilute 3.0 mL of the test solution to 100.0 mL with methanol R. Dilute 1.0 mL of thi solution to 20.0 mL with methanol R.<\/p>\n Reference solution (b)\u00a0 Dissolve the contents of a vial of nebivolol impurity D CRS in 1 mL of the test solution.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n \u2014 stationary phase: amylose derivative of silica gel for chiral separation R (5 \u00b5m);<\/p>\n \u2014 temperature: 40 \u00b0C.<\/p>\n Mobile phase diethylamine R, ethanol (96 per cent) R (0.1:99.9 V\/V). Flow rate 1.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 280 nm.<\/p>\n Injection\u00a0 20 \u00b5L.<\/p>\n Run time\u00a0 3 times the retention time of nebivolol isomer 1.<\/p>\n Identification of impurities\u00a0 Use the chromatogram obtained with reference solution (b) to identify the peak due to impurity D.<\/p>\n Relative retention\u00a0 With reference to nebivolol isomer 1 (retention time = about 14 min): nebivolol isomer 2 = about 1.3; impurity D (isomer 1) = about 1.9; impurity D (isomer 2) = about 2.8.<\/p>\n System suitability\u00a0 Reference solution (b):<\/p>\n \u2014 resolution: minimum 2.0 between the peaks due to impurity D (isomer 1) and impurity D (isomer 2).<\/p>\n Calculation of percentage content:<\/p>\n \u2014 use the concentration of nebivolol hydrochloride (both isomers) in reference solution (a).<\/p>\n Limit:<\/p>\n \u2014 impurity D: maximum 0.3 per cent for the sum of the 2 isomers.<\/p>\n Liquid chromatography (2.2.29).<\/p>\n Solvent mixture\u00a0 acetonitrile R, water R (50:50 V\/V).<\/p>\n Test solution (a)\u00a0 Dissolve 20.0 mg of the substance to be examined in the solvent mixture and dilute to 10.0 mL with the solvent mixture.<\/p>\n Test solution (b)\u00a0 Dilute 1.0 mL of test solution (a) to 10.0 mL with the solvent mixture.<\/p>\n Reference solution (a)\u00a0 Dilute 1.0 mL of test solution (a) to 100.0 mL with the solvent mixture. Dilute 1.0 m of this solution to 10.0 mL with the solvent mixture.<\/p>\n Reference solution (b)\u00a0 Dissolve 10.0 mg of nebivolol hydrochloride CRS in the solvent mixture and dilute 50.0 mL with the solvent mixture.<\/p>\n Reference solution (c)\u00a0 Dissolve 2 mg of nebivolol for peak identification CRS (containing impurity A) in 1 mL of the solvent mixture.<\/p>\n Reference solution (d)\u00a0 Dissolve the contents of a vial of nebivolol impurity B CRS in 1 mL of reference solution (a).<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n \u2014 stationary phase: base-deactivated end-capped phenylsilyl silica gel for chromatography R (5 \u00b5m);<\/p>\n \u2014 temperature: 25 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: acetonitrile R, 3.4 g\/L solution of tetrabutylammonium hydrogen sulfate R (5:95 V\/V<\/p>\n \u2014 mobile phase B: water for chromatography R, acetonitrile R (5:95 V\/V);<\/p>\n Flow rate\u00a0 1.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 280 nm.<\/p>\n Injection\u00a0 10 \u00b5L of test solution (a) and reference solutions (a), (c) and (d).<\/p>\n Identification of impurities\u00a0 Use the chromatogram supplied with nebivolol for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peak due to impurity A; use the chromatogram obtained with reference solution (d) to identify the peak due to impurity B.<\/p>\n Relative retention\u00a0 With reference to nebivolol (retention time = about 19 min): impurity A = about 0.8; impurity B = about 1.1.<\/p>\n System suitability\u00a0 Reference solution (d):<\/p>\n \u2014 resolution: minimum 2.0 between the peaks due to nebivolol and impurity B.<\/p>\n Calculation of percentage content:<\/p>\n \u2014 for each impurity, use the concentration of nebivolol hydrochloride in reference solution (a).<\/p>\n Limits:<\/p>\n \u2014 impurities A, B: for each impurity, 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 Loss on drying (2.2.32)<\/strong><\/p>\n Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C for 3 h.<\/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 modifications.<\/p>\n Mobile phase:<\/p>\n Flow rate\u00a0 1.2 mL\/min.<\/p>\n Injection\u00a0 20 \u00b5L of test solution (b) and reference solution (b).<\/p>\n Retention time\u00a0 Nebivolol = about 12 minutes.<\/p>\n Calculate the percentage content of C22<\/sub>H26<\/sub>ClF2<\/sub>NO4<\/sub> taking into account the assigned content of nebivolol hydrochloride CRS.<\/p>\n Specified impurities\u00a0 A, B, 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). I is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10.<\/em><\/p>\n Control of impurities in substances for pharmaceutical use)\u00a0 C.<\/em><\/p>\n A. (1RS)-1-[(2RS)-3,4-dihydro-2H-1-benzopyran-2-yl]-2-[[(2RS)-2-[(2SR)-6-fluoro-3,4-dihydro-2H-1-\u00a0 benzopyran-2-yl]-2-hydroxyethyl]amino]ethan-1-ol,<\/p>\n B. (1RS,1\u2032RS)-2,2\u2032-azanediylbis[1-[(2SR)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]ethan-1-ol],<\/p>\n C. (1RS)-2-[benzyl[(2RS)-2-[(2RS)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]amino]-1-[(2SR)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]ethan-1-ol and (1RS)-2-[benzyl[(2SR)-2-[(2RS)-6-fluoro- 3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]amino]-1-[(2RS)-6-fluoro-3,4-dihydro-2H-1-benzopyran- yl]ethan-1-ol,<\/p>\n D. (1RS)-1-[(2RS)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-[[(2SR)-2-[(2RS)-6-fluoro-3,4-dihydro-2H\u00a0 1-benzopyran-2-yl]-2-hydroxyethyl]amino]ethan-1-ol.<\/p>\n Ph Eur<\/p>\n","protected":false},"excerpt":{"rendered":" Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Beta-adrenoceptor antagonist. Ph Eur DEFINITION (1RS)-1-[(2RS)-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-[[(2RS)-2-[(2SR)-6-fluoro-3,4-dihydro-2H-1-\u00a0 benzopyran-2-yl]-2-hydroxyethyl]amino]ethan-1-ol hydrochloride. Content 98.0 per cent to 102.0 per cent (dried substance). CHARACTERS Appearance White or almost white crystalline powder. Solubility Very slightly soluble in water, sparingly soluble in methanol, very slightly soluble in heptane. IDENTIFICATION A. Infrared absorption…<\/p>\n","protected":false},"author":5,"featured_media":25846,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-25845","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\/25845","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=25845"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/25845\/revisions"}],"predecessor-version":[{"id":25873,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/25845\/revisions\/25873"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/25846"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=25845"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=25845"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=25845"}],"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 D<\/h3>\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 – 18<\/td>\n 76<\/td>\n 24<\/td>\n<\/tr>\n \n 18 – 30<\/td>\n 76 \u2192 65<\/td>\n 24 \u2192 35<\/td>\n<\/tr>\n \n 30 – 45<\/td>\n 65<\/td>\n 35<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n ASSAY<\/h2>\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 – 15<\/td>\n 74<\/td>\n 26<\/td>\n<\/tr>\n \n 15 – 20<\/td>\n 74 \u2192 30<\/td>\n 26 \u2192 70<\/td>\n<\/tr>\n \n 20 – 25<\/td>\n 30<\/td>\n 70<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n IMPURITIES<\/h2>\n
\n