EUROPEAN PHARMACOPOEIA 5.8 Thioridazine Detection: spectrophotometer at 240 nm. C. R = CO-C2H5 : testosterone propionate, Injection: 20 µl of the test solution and reference β D. R = CO-CH(CH3)2 : 3-oxoandrost-4-en-17 -yl solutions (a) and (b). 2-methylpropanoate (testosterone isobutyrate), Run time: twice the retention time of testosterone β isocaproate. E. R = CO-[CH2]4-CH3 : 3-oxoandrost-4-en-17 -yl hexanoate (testosterone caproate), Identification of impurities: use the chromatogram supplied with testosterone isocaproate for system suitability CRS F. R = CO-[CH2]5-CH3 : testosterone enantate, and the chromatogram obtained with reference solution (a) toidentifythepeaksduetoimpuritiesA,B,C,D,E,FandG. Relative retention with reference to testosterone isocaproate (retention time = about 14 min): impurity A = about 0.2; impurity B = about 0.4; impurity C = about 0.5; impurity D = about 0.7; impurity G = about 0.8; impurity E = about 1.1; impurity F = about 1.4. System suitability: reference solution (a): G. 3-oxoandrost-4-en-17α-yl 4-methylpentanoate — peak-to-valley ratio: minimum 2.5, where Hp =height abovethebaselineofthepeakduetoimpurityEand (epitestosterone isocaproate). Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to testosterone isocaproate. 07/2007:2005 Limits: — impurities A, B, C, D, E, F, G:foreachimpurity,notmore THIORIDAZINE than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent); Thioridazinum — unspecified impurities: for each impurity, not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent); — total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent); — disregard limit: 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (b) C H N S M 370.6 (0.05 per cent). 21 26 2 2 r Free acid. Dissolve 0.44 g in 10 ml of ethanol (96 per DEFINITION cent) R, previously neutralised to bromothymol blue 10-[2-[(2RS)-1-Methylpiperidin-2-yl]ethyl]-2- solution R3, and titrate immediately with 0.01 M sodium (methylsulphanyl)-10H-phenothiazine hydroxide,using0.1mlofbromothymol blue solution R3 as Content: 99.0 per cent to 101.0 per cent (dried substance). indicator. Not more than 0.6 ml of 0.01 M sodium hydroxide is required to change the colour of the indicator to blue. CHARACTERS Loss on drying (2.2.32): maximum 0.5 per cent, determined Appearance:whiteoralmostwhitepowder. on 1.000 g over diphosphorus pentoxide R at a pressure Solubility: practically insoluble in water, very soluble in not exceeding 0.7 kPa. methylenechloride,freelysolubleinmethanol,solublein ethanol (96 per cent). ASSAY Liquid chromatography (2.2.29) as described in the test for IDENTIFICATION related substances with the following modification. Infrared absorption spectrophotometry (2.2.24). Injection: 20 µl of the test solution and reference solution (c). Comparison: thioridazine CRS. Calculate the percentage content of C H O from the 25 38 3 TESTS declared content of testosterone isocaproate CRS. Solution S. Dissolve 1.25 g in methanol R and dilute to IMPURITIES 25 ml with the same solvent. Specified impurities: A, B, C, D, E, F, G. Appearance of solution. Solution S is clear (2.2.1)andnot more intensely coloured than intensity 6 of the range of reference solutions of the most appropriate colour (2.2.2, Method II). Related substances.Liquidchromatography(2.2.29). Carry out the test as quickly as possible and protected from light. Test solution. Dissolve 20 mg of the substance to be examined in methanol R anddiluteto100mlwiththesame solvent. A. R = H: testosterone, Reference solution (a).Dilute5.0mlofthetestsolutionto β B. R =CO-CH3 : 3-oxoandrost-4-en-17 -yl acetate 100.0 ml with methanol R. Dilute 2.0 ml of this solution to (testosterone acetate), 100.0 ml with methanol R. GeneralNotices(1)applytoallmonographsandothertexts 5381 Tranexamic acid EUROPEAN PHARMACOPOEIA 5.8 Reference solution (b). Dissolve the contents of a vial ASSAY of thioridazine for system suitability CRS (containing Dissolve 0.300 g in 60 ml of anhydrous acetic acid R.Titrate impurities A, B, C, D and E) in 1.0 ml of methanol R. with 0.1 M perchloric acid, determining the end-point Column: potentiometrically (2.2.20). — size: l =0.25m,Ø=4.0mm; 1mlof0.1 M perchloric acid is equivalent to 37.06 mg of C H N S . — stationary phase: end-capped octadecylsilyl silica gel 21 26 2 2 for chromatography R resistant to bases up to pH 11. STORAGE Mobile phase: Protected from light. — mobile phase A: triethylamine R1, acetonitrile R, IMPURITIES water R (2:400:600 V/V/V); Specified impurities: A, B, C, D, E. — mobile phase B: triethylamine R1, acetonitrile R Other detectable impurities (the following substances (2:1000 V/V); would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited Time Mobile phase A Mobile phase B by the general acceptance criterion for other/unspecified (min) (per cent V/V) (per cent V/V) impurities and/or by the general monograph Substances for 0-5 100 0 pharmaceutical use (2034).Itisthereforenotnecessaryto 5 - 35 100 → 50→ 95 identify these impurities for demonstration of compliance. 35 - 40 5 95 See also 5.10. Control of impurities in substances for pharmaceutical use): F. 40 - 41 5 → 100 95 → 0 41 100 0 Flow rate:1.0ml/min. Detection: spectrophotometer at 275 nm. Injection:25µl. Identification of impurities:usethechromatogram supplied with thioridazine for system suitability CRS and ′ A. R = CH3,X=X =SO2 : 10-[2-[(2RS)-1-methylpiperidin- the chromatogram obtained with reference solution (b) to 2-yl]ethyl]-2-(methylsulphonyl)-10H-phenothiazine identify the peaks due to impurities A, B, C, D and E. 5,5-dioxide, Relative retention with reference to thioridazine ′ B. R = CH3,X=SO,X = S: 10-[2-[(2RS)-1-methylpiperidin- (retention time = about 30 min): impurity D = about 0.1; 2-yl]ethyl]-2-(methylsulphinyl)-10H-phenothiazine impurity A = about 0.3; impurity C = about 0.4; (mesoridazine), impurity B = about 0.5; impurity E = about 0.6. ′ System suitability: reference solution (b): C. R = CH3,X=S,X = SO: 10-[2-[(2RS)-1-methylpiperidin-2- yl]ethyl]-2-(methylsulphanyl)-10H-phenothiazine 5-oxide, — resolution : minimum 3.5 between the peaks due to ′ impurities C and B. D. R = CH3,X=X = SO: 10-[2-[(2RS)-1-methylpiperidin-2- yl]ethyl]-2-(methylsulphinyl)-10H-phenothiazine 5-oxide, Limits: ′ — correction factors: for the calculation of content, E. R = CH3,X=SO2,X = S: 10-[2-[(2RS)-1-methylpiperidin- multiply the peak areas of the following impurities by 2-yl]ethyl]-2-(methylsulphonyl)-10H-phenothiazine the corresponding correction factor: impurity A = 1.9; (sulforidazine), impurity B = 2.4; impurity C = 0.5; impurity D = 1.5; F. R = H, X = X′ = S: 2-(methylsulphanyl)-10-[2-[(2RS)- — impurities A, B, C, D, E: for each impurity, not more piperidin-2-yl]ethyl]-10H-phenothiazine (northioridazine). than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent); — unspecified impurities: for each impurity, not more 07/2007:0875 than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent); TRANEXAMIC ACID — total: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) Acidum tranexamicum (0.5 per cent); — disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent). Heavy metals (2.4.8): maximum 20 ppm. 1.0 g complies with test C. Prepare the reference solution using 2 ml of lead standard solution (10 ppm Pb) R. C8H15NO2 Mr 157.2 Loss on drying (2.2.32): maximum 0.5 per cent, determined on 1.000 g in vacuo at 50 °C for 4 h. DEFINITION Sulphated ash (2.4.14): maximum 0.1 per cent, determined trans-4-(Aminomethyl)cyclohexanecarboxylic acid. on 1.0 g. Content: 99.0 per cent to 101.0 per cent (dried substance). 5382 See the information section on general monographs (cover pages).