{"id":16401,"date":"2025-10-21T09:53:29","date_gmt":"2025-10-21T02:53:29","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=16401"},"modified":"2025-10-21T09:53:29","modified_gmt":"2025-10-21T02:53:29","slug":"ketotifen-fumarate","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/ketotifen-fumarate\/","title":{"rendered":"Ketotifen Fumarate"},"content":{"rendered":"

(Ketotifen Hydrogen Fumarate, Ph. Eur. monograph 1592)<\/p>\n

C_{23<\/sub>H_{23<\/sub>NO_{5<\/sub>S\u00a0 \u00a0 \u00a0 \u00a0425.5\u00a0 \u00a0 \u00a0 \u00a034580-14-8<\/p>\n}}}

Action and use<\/strong><\/p>\n

Histamine H1 receptor antagonist.<\/p>\n

DEFINITION<\/h2>\n
4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one hydrogen (E)- butenedioate.<\/p>\n
Content<\/h3>\n
98.5 per cent to 101.0 per cent (dried substance).<\/p>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
White or brownish-yellow, fine, crystalline powder.<\/p>\n
Solubility<\/h3>\n
Sparingly soluble in water, slightly soluble in methanol, practically insoluble in heptane.<\/p>\n
IDENTIFICATION<\/h2>\n
Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison: ketotifen hydrogen fumarate CRS.<\/p>\n
TESTS<\/h2>\n
Appearance of solution<\/h3>\n
The solution is clear (2.2.1) and not more intensely coloured than reference solution Y_{4<\/sub>, BY_{4<\/sub> or B_{4<\/sub> (2.2.2, Method II).<\/p>\n}}}
Dissolve 0.2 g in methanol R and dilute to 10 mL with the same solvent.<\/p>\n
Related substances<\/h3>\n
Liquid chromatography (2.2.29). Carry out the test protected from light.<\/p>\n
Solvent mixture: methanol R, water R (50:50 V\/V).<\/p>\n
Test solution: Dissolve 30.0 mg of the substance to be examined in the solvent mixture and dilute to 100.0 mL with the solvent mixture.<\/p>\n
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
Reference solution (b): Dissolve the contents of a vial of ketotifen impurity G CRS in 1.0 mL of a solution prepared as follows: mix 1.0 mL of the test solution with 9.0 mL of the solvent mixture. Sonicate until dissolution of impurity G is complete.<\/p>\n
Reference solution (c): Dissolve 5 mg of ketotifen for peak identification CRS (containing impurity A) in the solvent mixture and dilute to 5.0 mL with the solvent mixture.<\/p>\n
Column:<\/p>\n
\u2014 size: l = 0.15 m, \u00d8 = 4.0 mm;<\/p>\n
\u2014 stationary phase: base-deactivated end-capped octadecylsilyl silica gel for chromatography R (3 \u03bcm);<\/p>\n
\u2014 temperature: 40 \u00b0C.<\/p>\n
Mobile phase:<\/p>\n
\u2014 mobile phase A: mix 175 \u03bcL of triethylamine R and 500 mL of water R;<\/p>\n
\u2014 mobile phase B: mix 175 \u03bcL of triethylamine R and 500 mL of methanol R;<\/p>\n\n\n\n\n\n\n
Time<\/strong>
\n(min)<\/strong><\/td>\n Mobile phase A<\/strong>
\n(per cent V\/V)<\/strong><\/td>\n Mobile phase B<\/strong>
\n(per cent V\/V)<\/strong><\/td>\n<\/tr>\n
0 – 12<\/td>\n 40<\/td>\n 60<\/td>\n<\/tr>\n
12 – 20<\/td>\n 40 \u2192 10<\/td>\n 60 \u2192 90<\/td>\n<\/tr>\n
20 – 25<\/td>\n 10<\/td>\n 90<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Flow rate: 1.0 mL\/min.<\/p>\n
Detection: Spectrophotometer at 297 nm.<\/p>\n
Injection: 20 \u03bcL.<\/p>\n
Identification of impurities: Use the chromatogram supplied with ketotifen 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 (b) to identify the peak due to impurity G.<\/p>\n
Relative retention: With reference to ketotifen (retention time = about 11 min): fumaric acid = about 0.1; impurity G = about 0.8; impurity A = about 1.9.<\/p>\n
System suitability: Reference solution (b):<\/p>\n
\u2014 resolution: minimum 1.5 between the peaks due to impurity G and ketotifen.<\/p>\n
Limits:<\/p>\n
\u2014 correction factor: for the calculation of content, multiply the peak area of impurity G by 1.4;<\/p>\n
\u2014 impurity A: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);<\/p>\n
\u2014 impurity G: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent);<\/p>\n
\u2014 unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);<\/p>\n
\u2014 total: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent);<\/p>\n
\u2014 disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent); disregard the peak due to fumaric acid.<\/p>\n
Loss on drying (2.2.32)<\/h4>\n
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C for 4 h.<\/p>\n
Sulfated ash (2.4.14)<\/h4>\n
Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n
ASSAY<\/h2>\n
Dissolve 0.350 g in a mixture of 30 mL of acetic anhydride R and 30 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).<\/p>\n
1 mL of 0.1 M perchloric acid is equivalent to 42.55 mg of C_{23<\/sub>H_{23<\/sub>NO_{5<\/sub>S.<\/p>\n}}}
IMPURITIES<\/h2>\n
Specified impurities A, G.<\/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, C, D, E, F.<\/p>\n
$\"Ketotifen$ <\/p>\n
A. 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine,<\/p>\n
$\"Ketotifen$ <\/p>\n
B. (4RS)-10-methoxy-4-(1-methylpiperidin-4-yl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol,<\/p>\n
$\"Ketotifen$ <\/p>\n
C. (4RS)-4-hydroxy-4-(1-methylpiperidin-4-yl)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10- one,<\/p>\n
$\"Ketotifen$ <\/p>\n
D. 4-[(RaSa)-1-methylpiperidin-4-ylidene]-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one N-oxide (ketotifen N-oxide),<\/p>\n
$\"Ketotifen$ <\/p>\n
E. 10-(1-methylpiperidin-4-ylidene)-5,10-dihydro-4H-benzo[5,6]cyclohepta[1,2-b]thiophen-4-one,<\/p>\n
$\"Ketotifen$ <\/p>\n
F. 4-(1-methylpiperidin-4-ylidene)-4,10-dihydro-9H-benzo[4,5]cyclohepta[1,2-b]thiophen-9-one,<\/p>\n
$\"Ketotifen$ <\/p>\n
G. 4-(1-methylpiperidin-4-ylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9,10-dione.<\/p>\n","protected":false},"excerpt":{"rendered":"
(Ketotifen Hydrogen Fumarate, Ph. Eur. monograph 1592) C23H23NO5S\u00a0 \u00a0 \u00a0 \u00a0425.5\u00a0 \u00a0 \u00a0 \u00a034580-14-8 Action and use Histamine H1 receptor antagonist. DEFINITION 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one hydrogen (E)- butenedioate. Content 98.5 per cent to 101.0 per cent (dried substance). CHARACTERS Appearance White or brownish-yellow, fine, crystalline powder. Solubility Sparingly soluble in water, slightly soluble in methanol, practically insoluble…<\/p>\n","protected":false},"author":2,"featured_media":16684,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-16401","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\/16401","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\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=16401"}],"version-history":[{"count":3,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/16401\/revisions"}],"predecessor-version":[{"id":16696,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/16401\/revisions\/16696"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/16684"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=16401"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=16401"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=16401"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

Time<\/strong> \n(min)<\/strong><\/td>\n	Mobile phase A<\/strong> \n(per cent V\/V)<\/strong><\/td>\n	Mobile phase B<\/strong> \n(per cent V\/V)<\/strong><\/td>\n<\/tr>\n
0 – 12<\/td>\n	40<\/td>\n	60<\/td>\n<\/tr>\n
12 – 20<\/td>\n	40 \u2192 10<\/td>\n	60 \u2192 90<\/td>\n<\/tr>\n
20 – 25<\/td>\n	10<\/td>\n	90<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n Flow rate: 1.0 mL\/min.<\/p>\n Detection: Spectrophotometer at 297 nm.<\/p>\n Injection: 20 \u03bcL.<\/p>\n Identification of impurities: Use the chromatogram supplied with ketotifen 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 (b) to identify the peak due to impurity G.<\/p>\n Relative retention: With reference to ketotifen (retention time = about 11 min): fumaric acid = about 0.1; impurity G = about 0.8; impurity A = about 1.9.<\/p>\n System suitability: Reference solution (b):<\/p>\n \u2014 resolution: minimum 1.5 between the peaks due to impurity G and ketotifen.<\/p>\n Limits:<\/p>\n \u2014 correction factor: for the calculation of content, multiply the peak area of impurity G by 1.4;<\/p>\n \u2014 impurity A: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);<\/p>\n \u2014 impurity G: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent);<\/p>\n \u2014 unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);<\/p>\n \u2014 total: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent);<\/p>\n \u2014 disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent); disregard the peak due to fumaric acid.<\/p>\n Loss on drying (2.2.32)<\/h4>\n Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C for 4 h.<\/p>\n Sulfated ash (2.4.14)<\/h4>\n Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n ASSAY<\/h2>\n Dissolve 0.350 g in a mixture of 30 mL of acetic anhydride R and 30 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).<\/p>\n 1 mL of 0.1 M perchloric acid is equivalent to 42.55 mg of C_{23<\/sub>H_{23<\/sub>NO_{5<\/sub>S.<\/p>\n}}} IMPURITIES<\/h2>\n Specified impurities A, G.<\/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, C, D, E, F.<\/p>\n $\"Ketotifen$ <\/p>\n A. 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidine,<\/p>\n $\"Ketotifen$ <\/p>\n B. (4RS)-10-methoxy-4-(1-methylpiperidin-4-yl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol,<\/p>\n $\"Ketotifen$ <\/p>\n C. (4RS)-4-hydroxy-4-(1-methylpiperidin-4-yl)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10- one,<\/p>\n $\"Ketotifen$ <\/p>\n D. 4-[(RaSa)-1-methylpiperidin-4-ylidene]-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one N-oxide (ketotifen N-oxide),<\/p>\n $\"Ketotifen$ <\/p>\n E. 10-(1-methylpiperidin-4-ylidene)-5,10-dihydro-4H-benzo[5,6]cyclohepta[1,2-b]thiophen-4-one,<\/p>\n $\"Ketotifen$ <\/p>\n F. 4-(1-methylpiperidin-4-ylidene)-4,10-dihydro-9H-benzo[4,5]cyclohepta[1,2-b]thiophen-9-one,<\/p>\n $\"Ketotifen$ <\/p>\n G. 4-(1-methylpiperidin-4-ylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9,10-dione.<\/p>\n","protected":false},"excerpt":{"rendered":" (Ketotifen Hydrogen Fumarate, Ph. Eur. monograph 1592) C23H23NO5S\u00a0 \u00a0 \u00a0 \u00a0425.5\u00a0 \u00a0 \u00a0 \u00a034580-14-8 Action and use Histamine H1 receptor antagonist. DEFINITION 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one hydrogen (E)- butenedioate. Content 98.5 per cent to 101.0 per cent (dried substance). CHARACTERS Appearance White or brownish-yellow, fine, crystalline powder. Solubility Sparingly soluble in water, slightly soluble in methanol, practically insoluble…<\/p>\n","protected":false},"author":2,"featured_media":16684,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-16401","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\/16401","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\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=16401"}],"version-history":[{"count":3,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/16401\/revisions"}],"predecessor-version":[{"id":16696,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/16401\/revisions\/16696"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/16684"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=16401"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=16401"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=16401"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

Content<\/h3>\n98.5 per cent to 101.0 per cent (dried substance).<\/p>\n

CHARACTERS<\/h2>\n

Appearance<\/h3>\nWhite or brownish-yellow, fine, crystalline powder.<\/p>\n

Solubility<\/h3>\nSparingly soluble in water, slightly soluble in methanol, practically insoluble in heptane.<\/p>\n

IDENTIFICATION<\/h2>\nInfrared absorption spectrophotometry (2.2.24).<\/p>\nComparison: ketotifen hydrogen fumarate CRS.<\/p>\n

TESTS<\/h2>\n

Appearance of solution<\/h3>\nThe solution is clear (2.2.1) and not more intensely coloured than reference solution Y4<\/sub>, BY4<\/sub> or B4<\/sub> (2.2.2, Method II).<\/p>\nDissolve 0.2 g in methanol R and dilute to 10 mL with the same solvent.<\/p>\n

Loss on drying (2.2.32)<\/h4>\nMaximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C for 4 h.<\/p>\n

Sulfated ash (2.4.14)<\/h4>\nMaximum 0.1 per cent, determined on 1.0 g.<\/p>\n

Content<\/h3>\n
98.5 per cent to 101.0 per cent (dried substance).<\/p>\n

Appearance<\/h3>\n
White or brownish-yellow, fine, crystalline powder.<\/p>\n

Solubility<\/h3>\n
Sparingly soluble in water, slightly soluble in methanol, practically insoluble in heptane.<\/p>\n

IDENTIFICATION<\/h2>\n
Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison: ketotifen hydrogen fumarate CRS.<\/p>\n

Appearance of solution<\/h3>\n
The solution is clear (2.2.1) and not more intensely coloured than reference solution Y_{4<\/sub>, BY_{4<\/sub> or B_{4<\/sub> (2.2.2, Method II).<\/p>\n}}}
Dissolve 0.2 g in methanol R and dilute to 10 mL with the same solvent.<\/p>\n

Loss on drying (2.2.32)<\/h4>\n
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C for 4 h.<\/p>\n

Sulfated ash (2.4.14)<\/h4>\n
Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n