Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n
Action and use<\/strong><\/p>\n Stimulates insulin release; treatment of diabetes mellitus.<\/p>\n Ph Eur<\/p>\n N-[[trans-4-(1-Methylethyl)cyclohexyl]carbonyl]-D-phenylalanine.<\/p>\n Content<\/strong><\/p>\n 98.0 per cent to 102.0 per cent (dried substance).<\/p>\n White or almost white powder.<\/p>\n Practically insoluble in water, freely soluble in methanol and in methylene chloride. It shows polymorphism (5.9).<\/p>\n Carry out either tests A, B or tests B, C.<\/p>\n A. Specific optical rotation (2.2.7): -40.0 to -36.5 (dried substance).<\/p>\n Dissolve 0.200 g in a 4 g\/L solution of sodium hydroxide R and dilute to 20.0 mL with the same solution.<\/p>\n B. Infrared absorption spectrophotometry (2.2.24).<\/p>\n Comparison\u00a0 nateglinide 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 methanol R, evaporate to dryness and record new spectra using the residues.<\/p>\n C. Test B for related substances (see Tests).<\/p>\n A. Impurity A and unspecified impurities. Liquid chromatography (2.2.29).<\/p>\n Test solution\u00a0 Dissolve 60.0 mg of the substance to be examined in 1 mL of acetonitrile R1 and dilute to 10.0 mL with the mobile phase.<\/p>\n Reference solution (a)\u00a0 Dissolve 3.0 mg of nateglinide impurity A CRS in 1 mL of acetonitrile R1 and dilute to 25.0 mL with the mobile phase.<\/p>\n Reference solution (b)\u00a0 Dilute 1.0 mL of reference solution (a) to 10.0 mL with the mobile phase.<\/p>\n Reference solution (c)\u00a0 Dissolve 3 mg of the substance to be examined in 1 mL of acetonitrile R1, add 4.0 mL of reference solution (a) and dilute to 10 mL with the mobile phase.<\/p>\n Reference solution (d)\u00a0 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 = 0.05 m, \u00d8 = 3.9 mm;<\/p>\n \u2014 stationary phase: spherical end-capped octylsilyl silica gel for chromatography R (5 \u00b5m);<\/p>\n \u2014 temperature: 40 \u00b0C.<\/p>\n Mobile phase\u00a0 Mix 35 volumes of acetonitrile R1 and 65 volumes of a 7.8 g\/L solution of sodium dihydrogen phosphate monohydrate R previously adjusted to pH 2.5 with phosphoric acid R.<\/p>\n Flow rate\u00a0 2.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 210 nm.<\/p>\n Injection\u00a0 100 \u00b5L of the test solution and reference solutions (b), (c) and (d).<\/p>\n Run time\u00a0 5 times the retention time of nateglinide.<\/p>\n Relative retention\u00a0 With reference to nateglinide (retention time = about 7 min): impurity A = about 0.5.<\/p>\n System suitability\u00a0 Reference solution (c):<\/p>\n \u2014 resolution: minimum 5.0 between the peaks due to impurity A and nateglinide.<\/p>\n Limits:<\/p>\n \u2014 impurity A: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (b) (0.2 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 (d) (0.10 per cent);<\/p>\n \u2014 sum of unspecified impurities: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (d) (0.2 per cent);<\/p>\n \u2014 disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (d) (0.05 per cent).<\/p>\n B. Impurity B. Liquid chromatography (2.2.29).<\/p>\n Test solution\u00a0 Dissolve 0.200 g of the substance to be examined in methanol R2 and dilute to 20.0 mL with the same solvent.<\/p>\n Reference solution (a)\u00a0 Dissolve 5 mg of nateglinide impurity B CRS in methanol R2 and dilute to 10.0 mL with the same solvent.<\/p>\n Reference solution (b)\u00a0 Dilute 1.0 mL of the test solution to 50.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.<\/p>\n Reference solution (c)\u00a0 Dissolve 0.10 g of the substance to be examined in methanol R2. Add 1.0 mL of reference solution (a) and dilute to 10.0 mL with methanol R2.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.0 mm;<\/p>\n \u2014 stationary phase: urea ty pe silica gel for chiral chromatography R (5 \u00b5m);<\/p>\n \u2014 temperature: 40 \u00b0C.<\/p>\n Mobile phase\u00a0 Dissolve 0.77 g of ammonium acetate R in methanol R2 and dilute to 1000 mL with the same solvent.<\/p>\n Flow rate\u00a0 0.8 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 220 nm.<\/p>\n Injection\u00a0 10 \u00b5L of the test solution and reference solutions (b) and (c).<\/p>\n Run time\u00a0 1.5 times the retention time of nateglinide.<\/p>\n Relative retention\u00a0 With reference to nateglinide (retention time = about 21 min): impurity B = about 0.9.<\/p>\n System suitability\u00a0 Reference solution (c):<\/p>\n \u2014 peak-to-valley ratio: minimum 3, where Hp = height above the baseline of the peak due to impurity B and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to nateglinide.<\/p>\n Limit:<\/p>\n \u2014 impurity B: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent).<\/p>\n C. Impurities C and D. Liquid chromatography (2.2.29).<\/p>\n Sodium phosphate buffer\u00a0 Dissolve 8.5 g of anhydrous disodium hydrogen phosphate R in 950 mL of water R. Adjust to pH 7.5 with phosphoric acid R and dilute to 1000 mL with water R.<\/p>\n Test solution\u00a0 Dissolve 50.0 mg of the substance to be examined in 25 mL of methanol R2 and dilute to 50.0 mL with the mobile phase.<\/p>\n Reference solution (a)\u00a0 Dissolve 5.0 mg of phenylalanine CRS (impurity D) and 5 mg of nateglinide impurity C CRS in methanol R2 and dilute to 25.0 mL with the same solvent.<\/p>\n Reference solution (b)\u00a0 Dilute 1.0 mL of the test solution to 50.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.<\/p>\n Reference solution (c)\u00a0 Dissolve 20 mg of the substance to be examined in 10 mL of methanol R2, add 1.0 mL of reference solution (a) and dilute to 20.0 mL with sodium phosphate buffer.<\/p>\n Reference solution (d)\u00a0 Dilute 1.0 mL of reference solution (a) to 100.0 mL with the mobile phase.<\/p>\n Reference solution (e)\u00a0 Dissolve 50.0 mg of nateglinide CRS in 25 mL of methanol R2 and dilute to 50.0 mL with the mobile phase.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.15 m, \u00d8 = 6.0 mm;<\/p>\n \u2014 stationary phase: polymethacrylate gel R (6 \u00b5m);<\/p>\n \u2014 temperature: 30 \u00b0C.<\/p>\n Mobile phase methanol R2, sodium phosphate buffer (45:55 V\/V). Flow rate 1.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 210 nm.<\/p>\n Injection\u00a0 20 \u00b5L of the test solution and reference solutions (b), (c) and (d).<\/p>\n Run time\u00a0 1.4 times the retention time of nateglinide.<\/p>\n Identification of impurities\u00a0 Use the chromatogram obtained with reference solution (c) to identify the peaks due to impurities C and D.<\/p>\n Relative retention\u00a0 With reference to nateglinide (retention time = about 18 min): impurity D = about 0.2; impurity C = about 0.9.<\/p>\n System suitability\u00a0 Reference solution (c):<\/p>\n \u2014 peak-to-valley ratio: minimum 1.5, where Hp = height above the baseline of the peak due to impurity C and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to nateglinide.<\/p>\n Limits:<\/p>\n \u2014 impurity C: not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent);<\/p>\n \u2014 impurity D: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (d) (0.2 per cent).<\/p>\n Limits:<\/p>\n \u2014 total for impurities A, B, C, D and sum of unspecified impurities: maximum 0.5 per cent;<\/p>\n \u2014 disregard limit for impurities A, B, C and D: 0.05 per cent for each impurity.<\/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 2 h.<\/p>\n Sulfated ash (2.4.14)<\/strong><\/p>\n Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n Liquid chromatography (2.2.29) as described in test C for related substances with the following modification.<\/p>\n Injection\u00a0 Test solution and reference solution (e).<\/p>\n Calculate the percentage content of C19<\/sub>H27<\/sub>NO3<\/sub> taking into account the assigned content of nateglinide CRS.<\/p>\n Specified impurities\u00a0 A, B, C, 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). It 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 E, F, G.<\/em><\/p>\n A. trans-4-(1-methylethyl)cyclohexanecarboxylic acid,<\/p>\n B. N-[[trans-4-(1-methylethyl)cyclohexyl]carbonyl]-L-phenylalanine (L-phenylalanine isomer),<\/p>\n C. N-[[cis-4-(1-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine\u00a0 (cis-isomer),<\/p>\n D. (2S)-2-amino-3-phenylpropanoic acid (phenylalanine),<\/p>\n E. N-[(trans-4-ethylcyclohexyl)carbonyl]-D-phenylalanine,<\/p>\n F. N-[[trans-4-(1-methylethyl)cyclohexyl]carbonyl]-D-phenylalanyl-D-phenylalanine,<\/p>\n G. ethyl N-[[trans-4-(1-methylethyl)cyclohexyl]carbonyl]-D-phenylalaninate.<\/p>\n Ph Eur<\/p>\n","protected":false},"excerpt":{"rendered":" Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Stimulates insulin release; treatment of diabetes mellitus. Ph Eur DEFINITION N-[[trans-4-(1-Methylethyl)cyclohexyl]carbonyl]-D-phenylalanine. Content 98.0 per cent to 102.0 per cent (dried substance). CHARACTERS Appearance White or almost white powder. Solubility Practically insoluble in water, freely soluble in methanol and in methylene chloride. It shows polymorphism (5.9)….<\/p>\n","protected":false},"author":5,"featured_media":25783,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-25782","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\/25782","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=25782"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/25782\/revisions"}],"predecessor-version":[{"id":25798,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/25782\/revisions\/25798"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/25783"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=25782"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=25782"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=25782"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nDEFINITION<\/h2>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
Solubility<\/h3>\n
IDENTIFICATION<\/h2>\n
TESTS<\/h2>\n
Related substances<\/h3>\n
ASSAY<\/h2>\n
IMPURITIES<\/h2>\n
\n