{"id":25381,"date":"2025-11-04T14:35:22","date_gmt":"2025-11-04T07:35:22","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=25381"},"modified":"2025-11-04T14:35:22","modified_gmt":"2025-11-04T07:35:22","slug":"nilotinib-hydrochloride-monohydrate","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/nilotinib-hydrochloride-monohydrate\/","title":{"rendered":"Nilotinib Hydrochloride Monohydrate"},"content":{"rendered":"

(Ph. Eur. monograph 2993)<\/p>\n

C_{28<\/sub>H_{23<\/sub>ClF_{3<\/sub>N_{7<\/sub>O,H_{2<\/sub>O\u00a0 \u00a0 \u00a0 \u00a0 \u00a0584.0\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 923288-90-8<\/p>\n}}}}}

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

Tyrosine kinase (BCR-ABL) inhibitor; treatment of chronic myeloid leukaemia.<\/p>\n

DEFINITION<\/h2>\n
4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzamide hydrochloride monohydrate.<\/p>\n
Content<\/h3>\n
98.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
White or slightly yellowish or slightly greenish-yellow, hygroscopic, crystalline powder.<\/p>\n
Solubility<\/h3>\n
Practically insoluble in water, slightly soluble in anhydrous ethanol, very slightly soluble in heptane.<\/p>\n
It shows polymorphism (5.9).<\/p>\n
IDENTIFICATION<\/h2>\n
A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison: nilotinib hydrochloride 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 anhydrous ethanol R, evaporate to dryness and record new spectra using the residues.<\/p>\n
B. It gives reaction (b) of chlorides (2.3.1).\\<\/p>\n
C. Water (see Tests).<\/p>\n
TESTS<\/h2>\n
Impurity A<\/h3>\n
Liquid chromatography (2.2.29). Carry out the test protected from light.<\/p>\n
Solvent mixture: dimethyl sulfoxide R, water R (20:80 V\/V).<\/p>\n
Test solution: Dissolve 0.300 g of the substance to be examined in 2 mL of dimethyl sulfoxide R, add 7 mL of water R, allow to equilibrate at room temperature without shaking to avoid foam formation, and then dilute to 10.0 mL with water R. Shake well, allow the substance to be examined to precipitate for about 2 h in the dark and filter the supernatant through a 0.45 \u03bcm filter.<\/p>\n
Reference solution (a): Dissolve 7.5 mg of nilotinib impurity A CRS in dimethyl sulfoxide R and dilute to 100.0 mL with the same solvent. Dilute 1.0 mL of the solution to 100.0 mL with dimethyl sulfoxide R. Dilute 2.0 mL of this solution to 10.0 mL with water R.<\/p>\n
Reference solution (b): Dissolve 7.5 mg of nilotinib impurity B CRS and 7.5 mg of nilotinib impurity C CRS in dimethyl sulfoxide R and dilute to 100.0 mL with the same solvent. Dilute 1.0 mL of the solution to 100.0 mL with dimethyl sulfoxide R. Dilute 2.0 mL of this solution to 10.0 mL with water R.<\/p>\n
Reference solution (c): Dilute 2.0 mL of reference solution (b) to 10.0 mL with the solvent mixture.<\/p>\n
Column:<\/p>\n
\u2014 size: l = 0.15 m, \u00d8 = 3.0 mm;<\/p>\n
\u2014 stationary phase: encapsulated polar-embedded octadecylsilyl silica gel for chromatography R (3 \u03bcm);<\/p>\n
\u2014 temperature: 40 \u00b0C.<\/p>\n
Mobile phase:<\/p>\n
\u2014 mobile phase A: 1.36 g\/L solution of potassium dihydrogen phosphate R adjusted to pH 3.0 with phosphoric acid R;<\/p>\n
\u2014 mobile phase B: mobile phase A, acetonitrile R1 (20:80 V\/V);<\/p>\n\n\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 – 2<\/td>\n 85<\/td>\n 15<\/td>\n<\/tr>\n
2 – 10<\/td>\n 85 \u2192 80<\/td>\n 15 \u2192 20<\/td>\n<\/tr>\n
10 – 12<\/td>\n 80 \u2192 75<\/td>\n 20 \u2192 25<\/td>\n<\/tr>\n
12 – 18<\/td>\n 75 \u2192 10<\/td>\n 25 \u2192 90<\/td>\n<\/tr>\n
18 – 19<\/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 207 nm.<\/p>\n
Injection: 20 \u03bcL of the test solution and reference solution (a).<\/p>\n
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peak due to impurity A.<\/p>\n
Relative retention: With reference to nilotinib (retention time = about 17 min): impurity A = about 0.3.<\/p>\n
System suitability:<\/p>\n
\u2014 repeatability: maximum relative standard deviation of 5.0 per cent determined on 6 injections of reference solution (a).<\/p>\n
Calculation of content:<\/p>\n
\u2014 for impurity A, use the concentration of impurity A in reference solution (a).<\/p>\n
Limit:<\/p>\n
\u2014 impurity A: maximum 3 ppm.<\/p>\n
Impurities B and C<\/h3>\n
Liquid chromatography (2.2.29) as described in the test for impurity A with the following modifications.<\/p>\n
Detection: Spectrophotometer at 225 nm.<\/p>\n
Injection: Test solution and reference solutions (b) and (c).<\/p>\n
Identification of impurities: Use the chromatogram obtained with reference solution (b) to identify the peaks due to impurities B and C.<\/p>\n
Relative retention: With reference to nilotinib (retention time = about 17 min): impurity C = about 0.2; impurity B = about 0.6.<\/p>\n
System suitability:<\/p>\n
\u2014 signal-to-noise ratio: minimum 10 for the peaks due to impurities B and C in the chromatogram obtained with reference solution (c);<\/p>\n
\u2014 repeatability: maximum relative standard deviation of 5.0 per cent for the areas of the peaks due to impurities B and C, determined on 6 injections of reference solution (b).<\/p>\n
Calculation of contents:<\/p>\n
\u2014 for impurities B and C, use the concentration of the corresponding impurity in reference solution (b).<\/p>\n
Limits:<\/p>\n
\u2014 impurities B, C: for each impurity, maximum 2 ppm.<\/p>\n
Related substances<\/h3>\n
Liquid chromatography (2.2.29). Carry out the test protected from light.<\/p>\n
Solvent mixture: anhydrous ethanol R, water R (50:50 V\/V).<\/p>\n
Test solution: Dissolve 20.0 mg of the substance to be examined in the solvent mixture and dilute to 200.0 mL with the solvent mixture.<\/p>\n
Reference solution (a): Dissolve 20.0 mg of nilotinib hydrochloride monohydrate CRS in the solvent mixture and dilute to 200.0 mL with the solvent mixture.<\/p>\n
Reference solution (b): 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 (c): Dissolve 2 mg of nilotinib for system suitability CRS (containing impurities E, F and G) in the solvent mixture and dilute to 20 mL with the solvent mixture.<\/p>\n
Column:<\/p>\n
\u2014 size: l = 0.15 m, \u00d8 = 3.0 mm;<\/p>\n
\u2014 stationary phase: end-capped octadecylsilyl silica gel for chromatography compatible with 100 per cent aqueous mobile phases R (3 \u03bcm);<\/p>\n
\u2014 temperature: 40 \u00b0C.<\/p>\n
Mobile phase:<\/p>\n
\u2014 mobile phase A: 1.36 g\/L solution of potassium dihydrogen phosphate R adjusted to pH 3.0 with phosphoric acid R;<\/p>\n
\u2014 mobile phase B: mobile phase A, acetonitrile for chromatography R (20:80 V\/V);<\/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 – 2<\/td>\n 90<\/td>\n 10<\/td>\n<\/tr>\n
2 – 16<\/td>\n 90 \u2192 10<\/td>\n 10 \u2192 90<\/td>\n<\/tr>\n
16 – 17<\/td>\n 10<\/td>\n 90<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Flow rate: 0.8 mL\/min.<\/p>\n
Detection: Spectrophotometer at 240 nm.<\/p>\n
Injection: 5 \u03bcL of the test solution and reference solutions (b) and (c).<\/p>\n
Identification of impurities: Use the chromatogram supplied with nilotinib for system suitability CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities E, F and G.<\/p>\n
Relative retention: With reference to nilotinib (retention time = about 12 min): impurity E = about 1.03; impurity F = about 1.07; impurity G = about 1.09.<\/p>\n
System suitability: Reference solution (c):<\/p>\n
\u2014 resolution: minimum 1.5 between the peaks due to impurities F and G;<\/p>\n
\u2014 peak-to-valley ratio: minimum 2.0, where Hp = height above the baseline of the peak due to impurity E and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to nilotinib.<\/p>\n
Calculation of percentage contents:<\/p>\n
\u2014 for each impurity, use the concentration of nilotinib hydrochloride monohydrate in reference solution (b).<\/p>\n
Limits:<\/p>\n
\u2014 impurity F: maximum 0.2 per cent;<\/p>\n
\u2014 unspecified impurities: for each impurity, maximum 0.10 per cent;<\/p>\n
\u2014 total: maximum 0.40 per cent;<\/p>\n
\u2014 reporting threshold: 0.05 per cent.<\/p>\n
Water (2.5.12)<\/h4>\n
3.0 per cent to 5.0 per cent, determined on 0.150 g.<\/p>\n
Sulfated ash (2.4.14)<\/h4>\n
Maximum 0.1 per cent, determined on 1.0 g in a platinum crucible.<\/p>\n
ASSAY<\/h2>\n
Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.<\/p>\n
Injection Test solution and reference solution (a).<\/p>\n
Calculate the percentage content of C_{28<\/sub>H_{23<\/sub>ClF_{3<\/sub>N_{7<\/sub>O,H_{2<\/sub>O taking into account the assigned content of nilotinib hydrochloride monohydrate CRS.<\/p>\n}}}}}
STORAGE<\/h2>\n
In an airtight container.<\/p>\n
IMPURITIES<\/h2>\n
Specified impurities A, B, C, F.<\/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) D, E, G, H.<\/p>\n
$\"Nilotinib$ <\/p>\n
A. 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline,<\/p>\n
$\"Nilotinib$ <\/p>\n
B. methyl 3-amino-4-methylbenzoate,<\/p>\n
$\"Nilotinib$ <\/p>\n
C. 3-amino-4-methylbenzoic acid,<\/p>\n
$\"Nilotinib$ <\/p>\n
D. 4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzoic acid,<\/p>\n
$\"Nilotinib$ <\/p>\n
E. N-[3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzamide,<\/p>\n
$\"Nilotinib$ <\/p>\n
F. N-[3-(4-ethyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzamide,<\/p>\n
$\"Nilotinib$ <\/p>\n
G. methyl 4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzoate,<\/p>\n
$\"Nilotinib$ <\/p>\n
H. 4-methyl-N-[3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzamide.<\/p>\n","protected":false},"excerpt":{"rendered":"
(Ph. Eur. monograph 2993) C28H23ClF3N7O,H2O\u00a0 \u00a0 \u00a0 \u00a0 \u00a0584.0\u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 923288-90-8 Action and use Tyrosine kinase (BCR-ABL) inhibitor; treatment of chronic myeloid leukaemia. DEFINITION 4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzamide hydrochloride monohydrate. Content 98.0 per cent to 102.0 per cent (anhydrous substance). CHARACTERS Appearance White or slightly yellowish or slightly greenish-yellow, hygroscopic, crystalline powder. Solubility Practically…<\/p>\n","protected":false},"author":2,"featured_media":25439,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-25381","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\/25381","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=25381"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/25381\/revisions"}],"predecessor-version":[{"id":25441,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/25381\/revisions\/25441"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/25439"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=25381"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=25381"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=25381"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

Content<\/h3>\n98.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n

CHARACTERS<\/h2>\n

Appearance<\/h3>\nWhite or slightly yellowish or slightly greenish-yellow, hygroscopic, crystalline powder.<\/p>\n

Solubility<\/h3>\nPractically insoluble in water, slightly soluble in anhydrous ethanol, very slightly soluble in heptane.<\/p>\nIt shows polymorphism (5.9).<\/p>\n

TESTS<\/h2>\n

Water (2.5.12)<\/h4>\n3.0 per cent to 5.0 per cent, determined on 0.150 g.<\/p>\n

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

STORAGE<\/h2>\nIn an airtight container.<\/p>\n

Content<\/h3>\n
98.0 per cent to 102.0 per cent (anhydrous substance).<\/p>\n

Appearance<\/h3>\n
White or slightly yellowish or slightly greenish-yellow, hygroscopic, crystalline powder.<\/p>\n

Solubility<\/h3>\n
Practically insoluble in water, slightly soluble in anhydrous ethanol, very slightly soluble in heptane.<\/p>\n
It shows polymorphism (5.9).<\/p>\n

Water (2.5.12)<\/h4>\n
3.0 per cent to 5.0 per cent, determined on 0.150 g.<\/p>\n

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

STORAGE<\/h2>\n
In an airtight container.<\/p>\n