{"id":29059,"date":"2025-11-10T14:10:03","date_gmt":"2025-11-10T07:10:03","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=29059"},"modified":"2025-11-10T14:10:03","modified_gmt":"2025-11-10T07:10:03","slug":"riociguat","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/riociguat\/","title":{"rendered":"Riociguat"},"content":{"rendered":"<p><em>(Ph. Eur. monograph 3078)<\/em><\/p>\n<p>C<sub>20<\/sub>H<sub>19<\/sub>FN<sub>8<\/sub>O<sub>2<\/sub> 422.4 625115-55-1<\/p>\n<p><strong>Action and use<\/strong><\/p>\n<p>Guanylate cyclase stimulator; treatment of pulmonary hypertension.<\/p>\n<p><strong>Preparation<\/strong><\/p>\n<p>Riociguat Tablets<\/p>\n<h2>DEFINITION<\/h2>\n<p>Methyl [4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl](methyl)carbamate.<\/p>\n<h3>Content<\/h3>\n<p>98.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n<h2>CHARACTERS<\/h2>\n<h3>Appearance<\/h3>\n<p>White or yellowish powder.<\/p>\n<h3>Solubility<\/h3>\n<p>Practically insoluble in water, very slightly soluble in anhydrous ethanol, practically insoluble in heptane.<\/p>\n<p>It shows polymorphism (5.9).<\/p>\n<h2>IDENTIFICATION<\/h2>\n<p>Infrared absorption spectrophotometry (2.2.24).<\/p>\n<p>Comparison: riociguat CRS.<\/p>\n<p>If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in methanol R, evaporate to dryness and record new spectra using the residues.<\/p>\n<h2>TESTS<\/h2>\n<p>Protect the solutions from light throughout the tests.<\/p>\n<h3>Related substances<\/h3>\n<p>Liquid chromatography (2.2.29).<\/p>\n<p>Solvent mixture: Mobile phase A, acetonitrile R (20:80 V\/V).<\/p>\n<p>Test solution: Dissolve 20.0 mg of the substance to be examined in the solvent mixture using sonication and dilute to 50.0 mL with the solvent mixture.<\/p>\n<p>Reference solution (a): Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.<\/p>\n<p>Reference solution (b): Dissolve 4 mg of riociguat for system suitability CRS (containing impurities B and C) in the solvent mixture using sonication and dilute to 10 mL with the solvent mixture.<\/p>\n<p>Reference solution (c): Dissolve 20.0 mg of riociguat CRS in the solvent mixture using sonication and dilute to 50.0 mL with the solvent mixture.<\/p>\n<p>Column:<\/p>\n<p>\u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n<p>\u2014 stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 \u03bcm);<\/p>\n<p>\u2014 temperature: 40 \u00b0C.<\/p>\n<p>Mobile phase:<\/p>\n<p>\u2014 mobile phase A: perchloric acid R, water for chromatography R (0.4:100 V\/V);<\/p>\n<p>\u2014 mobile phase B: acetonitrile R1;<\/p>\n<table style=\"border-collapse: collapse; width: 100%;\">\n<tbody>\n<tr>\n<td style=\"width: 33.3333%; text-align: center;\"><strong>Time<\/strong><br \/>\n<strong>(min)<\/strong><\/td>\n<td style=\"width: 33.3333%; text-align: center;\"><strong>Mobile phase A<\/strong><br \/>\n<strong>(per cent V\/V)<\/strong><\/td>\n<td style=\"width: 33.3333%; text-align: center;\"><strong>Mobile phase B<\/strong><br \/>\n<strong>(per cent V\/V)<\/strong><\/td>\n<\/tr>\n<tr>\n<td style=\"width: 33.3333%; text-align: center;\">0 &#8211; 2<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">75<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">25<\/td>\n<\/tr>\n<tr>\n<td style=\"width: 33.3333%; text-align: center;\">2 &#8211; 27<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">75 \u2192 65<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">25 \u2192 35<\/td>\n<\/tr>\n<tr>\n<td style=\"width: 33.3333%; text-align: center;\">27 &#8211; 42<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">65 \u2192 32<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">35 \u2192 68<\/td>\n<\/tr>\n<tr>\n<td style=\"width: 33.3333%; text-align: center;\">42 &#8211; 43<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">32 \u2192 10<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">68 \u2192 90<\/td>\n<\/tr>\n<tr>\n<td style=\"width: 33.3333%; text-align: center;\">43 &#8211; 52<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">10<\/td>\n<td style=\"width: 33.3333%; text-align: center;\">90<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>Flow rate: 1.0 mL\/min.<\/p>\n<p>Detection: Spectrophotometer at 210 nm.<\/p>\n<p>Autosampler: Set at 15 \u00b0C.<\/p>\n<p>Injection: 5 \u03bcL of the test solution and reference solutions (a) and (b).<\/p>\n<p>Identification of impurities: Use the chromatogram supplied with riociguat for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities B and C.<\/p>\n<p>Relative retention: With reference to riociguat (retention time = about 22 min): impurity B = about 0.97; impurity C = about 1.4.<\/p>\n<p>System suitability: Reference solution (b):<\/p>\n<p>\u2014 resolution: minimum 1.5 between the peaks due to impurity B and riociguat.<\/p>\n<p>Calculation of percentage contents:<\/p>\n<p>\u2014 for each impurity, use the concentration of riociguat in reference solution (a).<\/p>\n<p>Limits:<\/p>\n<p>\u2014 impurity C: maximum 0.20 per cent;<\/p>\n<p>\u2014 unspecified impurities: for each impurity, maximum 0.10 per cent;<\/p>\n<p>\u2014 total: maximum 0.3 per cent;<\/p>\n<p>\u2014 reporting threshold: 0.05 per cent.<\/p>\n<h3>Impurity E<\/h3>\n<p>Head-space gas chromatography (2.2.28).<\/p>\n<p>Test solution: Dissolve 50 mg of the substance to be examined in 1.0 mL of dimethyl sulfoxide R in a head-space vial.<\/p>\n<p>Reference solution: Dilute 50 \u03bcL of benzene R (impurity E) to 10.0 mL with dimethyl sulfoxide R. Dilute 11.5 \u03bcL of the solution to 10.0 mL with dimethyl sulfoxide R. Transfer 20 \u03bcL of this solution into a head-space vial and add 1.0 mL of dimethyl sulfoxide R.<br \/>\nColumn:<\/p>\n<p>\u2014 material: fused silica;<\/p>\n<p>\u2014 size: l = 60 m, \u00d8 = 0.32 mm;<\/p>\n<p>\u2014 stationary phase: macrogol 20 000 R (film thickness 0.5 \u03bcm).<\/p>\n<p>Carrier: gas helium for chromatography R.<\/p>\n<p>Flow rate: 3.3 mL\/min.<\/p>\n<p>Split ratio: 1:20.<\/p>\n<p>Static head-space conditions that may be used:<\/p>\n<p>\u2014 equilibration temperature: 100 \u00b0C;<\/p>\n<p>\u2014 equilibration time: 30 min;<\/p>\n<p>\u2014 transfer-line temperature: 120 \u00b0C;<\/p>\n<p>\u2014 pressurisation time: 30 s;<\/p>\n<p>\u2014 injection volume: 1.0 mL;<\/p>\n<p>\u2014 injection time: 1 min.<\/p>\n<p>Temperature:<\/p>\n<table style=\"border-collapse: collapse; width: 100%; height: 169px;\">\n<tbody>\n<tr style=\"height: 43px;\">\n<td style=\"width: 33.3333%; height: 43px;\"><\/td>\n<td style=\"width: 33.3333%; height: 43px; text-align: center;\"><strong>Time<\/strong><br \/>\n<strong>(min)<\/strong><\/td>\n<td style=\"width: 33.3333%; height: 43px; text-align: center;\"><strong>Temperature<\/strong><br \/>\n<strong>(\u00b0C)<\/strong><\/td>\n<\/tr>\n<tr style=\"height: 21px;\">\n<td style=\"width: 33.3333%; height: 21px;\">Column<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">0 &#8211; 10<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">40 \u2192 60<\/td>\n<\/tr>\n<tr style=\"height: 21px;\">\n<td style=\"width: 33.3333%; height: 21px;\"><\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">10 &#8211; 15<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">60<\/td>\n<\/tr>\n<tr style=\"height: 21px;\">\n<td style=\"width: 33.3333%; height: 21px;\"><\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">15 &#8211; 18.2<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">60 \u2192 140<\/td>\n<\/tr>\n<tr style=\"height: 21px;\">\n<td style=\"width: 33.3333%; height: 21px;\"><\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">18.2 &#8211; 35<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">140<\/td>\n<\/tr>\n<tr style=\"height: 21px;\">\n<td style=\"width: 33.3333%; height: 21px;\">Injection port<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\"><\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">120<\/td>\n<\/tr>\n<tr style=\"height: 21px;\">\n<td style=\"width: 33.3333%; height: 21px;\">Detector<\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\"><\/td>\n<td style=\"width: 33.3333%; height: 21px; text-align: center;\">250<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>Detection: Flame ionisation.<\/p>\n<p>Identification of impurities: Use the chromatogram obtained with the reference solution to identify the peak due to impurity E.<\/p>\n<p>Retention time: Impurity E = about 7.1 min.<\/p>\n<p>System suitability: Reference solution:<\/p>\n<p>\u2014 signal-to-noise ratio: minimum 15 for the peak due to impurity E.<\/p>\n<p>Limit:<\/p>\n<p>\u2014 impurity E: not more than the area of the corresponding peak in the chromatogram obtained with the reference solution (2 ppm).<\/p>\n<h3>Water (2.5.32)<\/h3>\n<p>Maximum 0.2 per cent, determined on 0.250 g using the evaporation technique at 150 \u00b0C.<\/p>\n<h3>Sulfated ash (2.4.14)<\/h3>\n<p>Maximum 0.1 per cent, determined on 1.0 g in a platinum crucible.<\/p>\n<h2>ASSAY<\/h2>\n<p>Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.<\/p>\n<p>Injection: Test solution and reference solution (c).<\/p>\n<p>Calculate the percentage content of C<sub>20<\/sub>H<sub>19<\/sub>FN<sub>8<\/sub>O<sub>2<\/sub> taking into account the assigned content of riociguat CRS.<\/p>\n<h2>IMPURITIES<\/h2>\n<p>Specified impurities C, E.<\/p>\n<p>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, B, D.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-medium wp-image-29101\" src=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/2-52-300x163.jpg\" alt=\"Riociguat \" width=\"300\" height=\"163\" srcset=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/2-52-300x163.jpg 300w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/2-52-1024x555.jpg 1024w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/2-52-768x416.jpg 768w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/2-52.jpg 1200w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/p>\n<p>A. methyl [4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]carbamate,<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-medium wp-image-29102\" src=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/3-51-300x163.jpg\" alt=\"Riociguat \" width=\"300\" height=\"163\" srcset=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/3-51-300x163.jpg 300w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/3-51-1024x555.jpg 1024w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/3-51-768x416.jpg 768w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/3-51.jpg 1200w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/p>\n<p>B. methyl [4,6-diamino-2-(1-benzyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl](methyl)carbamate,<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-medium wp-image-29103\" src=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/4-49-300x163.jpg\" alt=\"Riociguat \" width=\"300\" height=\"163\" srcset=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/4-49-300x163.jpg 300w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/4-49-1024x555.jpg 1024w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/4-49-768x416.jpg 768w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/4-49.jpg 1200w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/p>\n<p>C. methyl [4-amino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-(methylamino)pyrimidin-5-yl] (methyl)carbamate,<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-medium wp-image-29104\" src=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/5-46-300x163.jpg\" alt=\"Riociguat \" width=\"300\" height=\"163\" srcset=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/5-46-300x163.jpg 300w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/5-46-1024x555.jpg 1024w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/5-46-768x416.jpg 768w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/5-46.jpg 1200w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/p>\n<p>D. propan-2-yl [4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl](methyl)carbamate,<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-medium wp-image-29105\" src=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/6-37-300x163.jpg\" alt=\"Riociguat \" width=\"300\" height=\"163\" srcset=\"https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/6-37-300x163.jpg 300w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/6-37-1024x555.jpg 1024w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/6-37-768x416.jpg 768w, https:\/\/nhathuocngocanh.com\/bp\/wp-content\/uploads\/2025\/11\/6-37.jpg 1200w\" sizes=\"auto, (max-width: 300px) 100vw, 300px\" \/><\/p>\n<p>E. benzene.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>(Ph. Eur. monograph 3078) C20H19FN8O2 422.4 625115-55-1 Action and use Guanylate cyclase stimulator; treatment of pulmonary hypertension. Preparation Riociguat Tablets DEFINITION Methyl [4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl](methyl)carbamate. Content 98.0 per cent to 102.0 per cent (anhydrous substance). CHARACTERS Appearance White or yellowish powder. Solubility Practically insoluble in water, very slightly soluble in anhydrous ethanol, practically insoluble in heptane. It&#8230;<\/p>\n","protected":false},"author":4,"featured_media":29100,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-29059","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\/29059","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\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=29059"}],"version-history":[{"count":4,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29059\/revisions"}],"predecessor-version":[{"id":29107,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29059\/revisions\/29107"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/29100"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=29059"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=29059"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=29059"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}