氨甲环酸EP7.0[1]

Tranexamic acid EUROPEAN PHARMACOPOEIA 7.0 A. R = CH3: (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-(methoxycarbonyl)- 3-phenylpropyl]amino]propanoyl]octahydro-1H-indole-2- carboxylic acid (methyl ester derivative), B. R = CH(CH3)2 : (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-[(1-methyl- ethoxy)carbonyl]-3-phenylpropyl]amino]propanoyl]octa- hydro-1H-indole-2-carboxylic acid (isopropyl ester derivative), E. R = H: (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-carboxy-3- phenylpropyl]amino]propanoyl]octahydro-1H-indole-2- carboxylic acid (trandolaprilate), C. (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-3-cyclohexyl-1- (ethoxycarbonyl)propyl]amino]propanoyl]octahydro- 1H-indole-2-carboxylic acid (hexahydrotrandolapril), D. ethyl (2S)-2-[(3S,5aS,9aR,10aS)-3-methyl-1,4- dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl]-4- phenylbutanoate (trandolapril diketopiperazine), F. (2R,3aR,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3- phenylpropyl]amino]propanoyl]octahydro-1H-indole-2- carboxylic acid. 01/2008:0875 corrected 6.0 TRANEXAMIC ACID Acidum tranexamicum C8H15NO2 Mr 157.2 [1197-18-8] DEFINITION trans-4-(Aminomethyl)cyclohexanecarboxylic acid. Content : 99.0 per cent to 101.0 per cent (dried substance). CHARACTERS Appearance : white or almost white, crystalline powder. Solubility : freely soluble in water and in glacial acetic acid, practically insoluble in acetone and in ethanol (96 per cent). IDENTIFICATION Infrared absorption spectrophotometry (2.2.24). Preparation : discs. Comparison : tranexamic acid CRS. TESTS pH (2.2.3) : 7.0 to 8.0. Dissolve 2.5 g in carbon dioxide-free water R and dilute to 50 mL with the same solvent. Related substances. Liquid chromatography (2.2.29). Test solution. Dissolve 0.20 g of the substance to be examined in water R and dilute to 20.0 mL with the same solvent. Reference solution (a). Dilute 5.0 mL of the test solution to 100.0 mL with water R. Dilute 1.0 mL of this solution to 10.0 mL with water R. Reference solution (b). Dissolve 20 mg of tranexamic acid CRS (containing impurity C) in water R and dilute to 2 mL with the same solvent. Reference solution (c). Dissolve 12 mg of 4-aminomethylben- zoic acid R (impurity D) in water R and dilute to 100 mL with the same solvent. Dilute 1 mL of the solution to 50 mL with water R. Dilute 5 mL of this solution to 200 mL with water R. Column : — size : l = 0.25 m, Ø = 4.6 mm or l = 0.25 m, Ø = 6.0 mm; — stationary phase : octadecylsilyl silica gel for chromatography R (5 μm). Mobile phase : dissolve 11.0 g of anhydrous sodium dihydrogen phosphate R in 500 mL of water R and add 5 mL of triethylamine R and 1.4 g of sodium laurilsulfate R. Adjust to pH 2.5 with dilute phosphoric acid R and dilute to 600 mL with water R. Add 400 mL of methanol R and mix. Flow rate : 0.9 mL/min. Detection : spectrophotometer at 220 nm. Injection : 20 μL. Run time : 3 times the retention time of tranexamic acid. Identification of impurities : use the chromatogram supplied with tranexamic acid CRS and the chromatogram obtained with reference solution (b) to identify the peak due to impurity C ; use the chromatogram obtained with reference solution (c) to identify the peak due to impurity D. Relative retention with reference to tranexamic acid (retention time = about 13 min) : impurity C = about 1.1 ; impurity D = about 1.3 ; impurity B = about 1.5 ; impurity A = about 2.1. System suitability : reference solution (b) : — resolution : minimum 1.5 between the peaks due to tranexamic acid and impurity C. Limits : — correction factors : for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor : impurity B = 1.2 ; impurity C = 0.005 ; impurity D = 0.006 ; — impurity A : not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent) ; — impurity B : not more than 0.4 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent) ; — unspecified impurities : for each impurity, not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent) ; — sum of unspecified impurities : not more than 0.4 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent) ; — disregard limit : 0.05 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.025 per cent). 3122 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 7.0 Trapidil Halides expressed as chlorides (2.4.4) : maximum 140 ppm. Dissolve 1.2 g in water R and dilute to 50 mL with the same solvent. Heavy metals (2.4.8) : maximum 10 ppm. Dissolve 2.0 g in water R and dilute to 20 mL with the same solvent. 12 mL of this solution complies with test A. Prepare the reference solution using lead standard solution (1 ppm Pb) R. Loss on drying (2.2.32) : maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 2 h. Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.140 g in 20 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20). 1 mL of 0.1 M perchloric acid is equivalent to 15.72 mg of C8H15NO2. IMPURITIES Specified impurities : A, B. 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) : C, D. A. trans,trans-4,4′-(iminodimethylene)di(cyclohexanecarboxylic) acid, B. cis-4-(aminomethyl)cyclohexanecarboxylic acid, C. (RS)-4-(aminomethyl)cyclohex-1-enecarboxylic acid, D. 4-aminomethylbenzoic acid. 01/2008:1576 TRAPIDIL Trapidilum C10H15N5 Mr 205.3 [15421-84-8] DEFINITION N,N-Diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine. Content : 99.0 per cent to 101.0 per cent (dried substance). CHARACTERS Appearance : white or almost white, crystalline powder. Solubility : freely soluble in water, soluble in ethanol and in methylene chloride. mp: about 102 °C. IDENTIFICATION Infrared absorption spectrophotometry (2.2.24). Comparison : trapidil CRS. TESTS Solution S. Dissolve 2.0 g in carbon dioxide-free water R and dilute to 100 mL with the same solvent. Appearance of solution. Solution S is clear (2.2.1) and colourless (2.2.2, Method II). Acidity or alkalinity. To 10 mL of solution S add 0.2 mL of methyl red solution R and 0.2 mL of 0.01 M hydrochloric acid. The solution is red. Add 0.4 mL of 0.01 M sodium hydroxide. The solution is yellow. Related substances. Liquid chromatography (2.2.29). Test solution. Dissolve 20.0 mg of the substance to be examined in the mobile phase and dilute to 10.0 mL with the mobile phase. Reference solution (a). Dissolve 5.0 mg of trapidil impurity A CRS in the mobile phase and dilute to 50.0 mL with the mobile phase. Dilute 1.0 mL of the solution to 50.0 mL with the mobile phase. Reference solution (b). Dissolve 5.0 mg of trapidil impurity B CRS in the mobile phase and dilute to 50.0 mL with the mobile phase. Dilute 1.0 mL of the solution to 50.0 mL with the mobile phase. Reference solution (c). Mix equal volumes of reference solution (a) and reference solution (b). Column : — size : l = 0.125 m, Ø = 4.0 mm, — stationary phase : base-deactivated octadecylsilyl silica gel for chromatography R (5 μm), Mobile phase : 50 mL of methanol R, 75 mL of acetonitrile R and 800 mL of a 1.7 g/L solution of potassium dihydrogen phosphate R adjusted to pH 2.45 with phosphoric acid R ; dilute to 1000 mL with water R. Flow rate : 1.0 mL/min. Detection : spectrophotometer at 205 nm. Injection : 10 μL. Run time : 3 times the retention time of trapidil. System suitability : — resolution : minimum of 4.0 between the peaks due to impurity A and impurity B in the chromatogram obtained with reference solution (c). General Notices (1) apply to all monographs and other texts 3123 2_Volume2_E.pdf 45-T-E toc Tranexamic acid Acidum tranexamicum DEFINITION CHARACTERS IDENTIFICATION TESTS pH (2.2.3): 7.0 to 8.0. Related substances. Liquid chromatography (2.2.29). Halides expressed as chlorides (2.4.4): maximum 140 ppm. Heavy metals (2.4.8): maximum 10 ppm. Loss on drying (2.2.32): maximum 0.5 per cent, determined on 1.0 Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g ASSAY IMPURITIES Trapidil Trapidilum DEFINITION CHARACTERS IDENTIFICATION TESTS Solution S. Dissolve 2.0 g in carbon dioxide-free water R and di Appearance of solution. Solution S is clear (2.2.1) and colourle Acidity or alkalinity. To 10 mL of solution S add 0.2 mL of meth Related substances. Liquid chromatography (2.2.29).