Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n
Action and use<\/strong><\/p>\n Bisphosphonate; treatment of osteolytic lesions, hypercalcaemia.<\/p>\n Content<\/p>\n 99.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n White or almost white, crystalline powder.<\/p>\n Slightly soluble in water, practically insoluble in anhydrous ethanol and in heptane.<\/p>\n A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n Comparison\u00a0 zoledronic acid monohydrate CRS.<\/p>\n B. Water (see Tests).<\/p>\n The solution is clear (2.2.1) and not more intensely coloured than reference solution B7 or BY7 (2.2.2, Method II). Dissolve 0.5 g in a 4 g\/L solution of sodium hydroxide R and dilute to 50.0 mL with the same solution.<\/p>\n 1.8 to 2.8.<\/p>\n Dissolve 0.150 g in carbon dioxide-free water R and dilute to 50.0 mL with the same solvent. Sonicate for 10 min, if necessary.<\/p>\n Liquid chromatography (2.2.29).<\/p>\n Solution A Dissolve 10.8 g of sodium octanesulfonate R and 37 mg of sodium edetate R in water for chromatography R, add 10 mL of perchloric acid R and 2 mL of phosphoric acid R and dilute to 1000 mL with water for chromatography R.<\/p>\n Test solution\u00a0 Dissolve 40.0 mg of the substance to be examined in the mobile phase, sonicate for 30 min, and dilute to 20.0 mL with the mobile phase.<\/p>\n Reference solution (a)\u00a0 Dissolve 2 mg of zoledronic acid impurity A CRS, 5 mg of zoledronic acid impurity B CRS and 2 mg of sodium nitrate R in the mobile phase and dilute to 50 mL with the mobile phase. To 1 mL of the solution add 7 mL of the mobile phase and dilute to 20 mL with the test solution.<\/p>\n Reference solution (b) Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n \u2014 stationary phase: end-capped phenylhexylsilyl silica gel for chromatography R (5 \u00b5m);<\/p>\n \u2014 temperature: 20 \u00b0C.<\/p>\n Mobile phase acetonitrile R1, solution A (4:96 V\/V). Flow rate 0.6 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 215 nm.<\/p>\n Preconditioning\u00a0 Precondition the instrument and the column once before each series of injections as follows:<\/p>\n \u2014 instrument: rinse the instrument without a column with a 25 per cent V\/V solution of acetic acid R at 5 mL\/min for about 20 min. Then, rinse with water for chromatography R at 5 mL\/min for about 2 h;<\/p>\n \u2014 column: rinse the column with the mobile phase at 0.6 mL\/min for about 1 h. During the rinsing, inject the test solution 15 times, applying a run time of about 3 min for each injection.<\/p>\n Injection\u00a0 10 \u00b5L.<\/p>\n Run time\u00a0 5 times the retention time of zoledronic acid.<\/p>\n Identification of impurities Use the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A and B and the nitrate ion.<\/p>\n Relative retention With reference to zoledronic acid (retention time = about 6 min): nitrate = about 0.6; impurity B = about 0.7; impurity A = about 0.9.<\/p>\n System suitability\u00a0 Reference solution (a):<\/p>\n \u2014 resolution: minimum 1.5 between the peaks due to impurity A and zoledronic acid; minimum 1.5 between the peaks due to the nitrate ion and impurity B.<\/p>\n Calculation of percentage contents:<\/p>\n \u2014 correction factor: multiply the peak area of impurity B by 1.9;<\/p>\n \u2014 for each impurity, use the concentration of zoledronic acid monohydrate in reference solution (b).<\/p>\n Limits:<\/p>\n \u2014 impurity B: maximum 0.5 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, disregard the peak due to the nitrate ion.<\/p>\n Liquid chromatography (2.2.29).<\/p>\n Test solution\u00a0 Dissolve 50.0 mg of the substance to be examined in mobile phase B, sonicate if necessary, and dilute to 10.0 mL with mobile phase B.<\/p>\n Reference solution (a) Dissolve 95.0 mg of anhydrous sodium dihydrogen phosphate R and 79.0 mg of phosphorous acid R (impurity E) in water R and dilute to 100.0 mL with the same solvent.<\/p>\n Reference solution (b)\u00a0 Dissolve 34.0 mg of sodium chloride R in water R and dilute to 100.0 mL with the same solvent.<\/p>\n Reference solution (c) To 1.0 mL of reference solution (a) add 0.5 mL of reference solution (b) and dilute to 100.0 mL with mobile phase B.<\/p>\n Reference solution (d)\u00a0 Dilute 0.1 mL of reference solution (a) to 100 mL with mobile phase B.<\/p>\n Precolumn:<\/p>\n \u2014 size: l = 0.05 m, \u00d8 = 4.0 mm;<\/p>\n \u2014 stationary phase: anion-exchange resin R (13 \u00b5m).<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.0 mm;<\/p>\n \u2014 stationary phase: anion-exchange resin R (9 \u00b5m);<\/p>\n \u2014 temperature: 30 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: carbon dioxide-free water R;<\/p>\n \u2014 mobile phase B: 4.0 g\/L solution of sodium hydroxide R in carbon dioxide-free water R;<\/p>\n Flow rate\u00a0 1.0 mL\/min.<\/p>\n Detection\u00a0 Conductivity detector; use a self-regenerating anion suppressor.<\/p>\n Injection\u00a0 20 \u00b5L.<\/p>\n Identification of impurities Use the chromatogram obtained with reference solution (a) to identify the peaks due to impurities E and F; use the chromatogram obtained with reference solution (b) to identify the peak due to the chloride ion.<\/p>\n Relative retention With reference to chloride (retention time = about 5 min): impurity E = about 1.2; impurity F = about 3.4.<\/p>\n System suitability:<\/p>\n \u2014 resolution: minimum 1.5 between the peaks due to the chloride ion and impurity E in the chromatogram obtained with reference solution (c);<\/p>\n \u2014 signal-to-noise ratio: minimum 10 for the peak due to impurity F in the chromatogram obtained with reference solution (d).<\/p>\n Calculation of percentage contents:<\/p>\n \u2014 for each impurity, use the concentration of the corresponding impurity in reference solution (c).<\/p>\n Limits:<\/p>\n \u2014 impurities E, F: for each impurity, maximum 0.15 per cent.<\/p>\n 5.0 per cent to 7.5 per cent, determined on 0.100 g.<\/p>\n Dissolve 0.150 g in 50 mL of carbon dioxide-free water R. Sonicate for 10 min, if necessary. Titrate with 0.1 M sodium hydroxide, determining the end-point potentiometrically (2.2.20). Read the volume added at the 3rd inflexion point.<\/p>\n 1 mL of 0.1 M sodium hydroxide is equivalent to 9.07 mg of C5<\/sub>H10<\/sub>N2<\/sub>O7<\/sub>P2<\/sub>.<\/p>\n Specified impurities\u00a0 B, E, F.<\/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) A, C, D.<\/em><\/p>\n A. [1-(2-hydroxy-2,2-diphosphonoethyl)-1H-imidazol-3-ium-3-yl]acetate,<\/p>\n B. 1,3-bis(2-hydroxy-2,2-diphosphonoethyl)-1H-imidazol-3-ium,<\/p>\n C. 1H-imidazole,<\/p>\n D. (1H-imidazol-1-yl)acetic acid,<\/p>\n E. phosphonic acid (phosphorous acid),<\/p>\n F. phosphoric acid.<\/p>\n","protected":false},"excerpt":{"rendered":" Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Bisphosphonate; treatment of osteolytic lesions, hypercalcaemia. DEFINITION [1-Hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid) monohydrate. Content 99.0 per cent to 102.0 per cent (anhydrous substance). CHARACTERS Appearance White or almost white, crystalline powder. Solubility Slightly soluble in water, practically insoluble in anhydrous ethanol and in heptane. IDENTIFICATION A. Infrared absorption…<\/p>\n","protected":false},"author":5,"featured_media":31984,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-31983","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\/31983","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=31983"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/31983\/revisions"}],"predecessor-version":[{"id":31992,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/31983\/revisions\/31992"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/31984"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=31983"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=31983"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=31983"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}DEFINITION<\/h2>\n[1-Hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid) monohydrate.<\/p>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
Solubility<\/h3>\n
IDENTIFICATION<\/h2>\n
TESTS<\/h2>\n
Appearance of solution<\/h3>\n
pH (2.2.3)<\/h3>\n
Related substances<\/h3>\n
Impurities E and F<\/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 – 13<\/td>\n 80 \u2192 70<\/td>\n 20 \u2192 30<\/td>\n<\/tr>\n \n 13 – 17<\/td>\n 70 \u2192 60<\/td>\n 30 \u2192 40<\/td>\n<\/tr>\n \n 17 – 29<\/td>\n 60<\/td>\n 40<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n Water (2.5.12)<\/h3>\n
ASSAY<\/h2>\n
IMPURITIES<\/h2>\n