Valproic acid EUROPEAN PHARMACOPOEIA 7.0

Other detectable impurities (the following substances would, IDENTIFICATION if present at a sufficient level, be detected by one or other of First identification: B. the tests in the monograph. They are limited by the general Secondidentification:A,C,D. acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use A. Refractive index (2.2.5): 1.422 to 1.425. (2034). It is therefore not necessary to identify these impurities B. Infrared absorption spectrophotometry (2.2.24). for demonstration of compliance. See also 5.10. Control of Comparison: valproic acid CRS. impurities in substances for pharmaceutical use):D,E. C. Thin-layer chromatography (2.2.27). Test solution. Dissolve 50 mg of the substance to be examined in methanol R and dilute to 5 mL with the same solvent. Reference solution. Dissolve 50 mg of valproic acid CRS in methanol R anddiluteto5mLwiththesamesolvent. Plate: TLC silica gel plate R. Mobile phase: ether R, methylenechlorideR(50:50 V/V). A. R = D-Val, X = SO: (3aS,4R,5S,6S,8R,9R,9aR,10R)-6- ethenyl-5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro-3a,9- Application:2μL. propano-3aH-cyclopenta[8]annulen-8-yl [[2-[[(2R)-2-amino-3- Development:overapathof15cm. methylbutanoyl]amino]-1,1-dimethylethyl]sulfinyl]acetate Drying:inair. (valnemulin sulfoxide), Detection:spraywithbromocresol green solution R. B. R = H, X = S: (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl- Results: the principal spot in the chromatogram obtained 5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro- with the test solution is similar in position, colour and size 3a,9-propano-3aH-cyclopenta[8]annulen-8-yl to the principal spot in the chromatogram obtained with the [(2-amino-1,1-dimethylethyl]sulfanyl]acetate (dimethyl reference solution. cysteaminyl pleuromulin), D.To1mLadd3mLofdilute sodium hydroxide solution R. C. R = D-Val-D-Val, X = S: (3aS,4R,5S,6S,8R,9R,9aR,10R)- Add 3 mL of water R and 1 mL of a 100 g/L solution of 6-ethenyl-5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro- cobalt nitrate R. A violet precipitate is formed. Filter. The 3a,9-propano-3aH-cyclopenta[8]annulen-8-yl precipitate dissolves in methylenechlorideR. [[2-[[(2R)-2-[[(2R)-2-amino-3-methylbutanoyl]amino]- 3-methylbutanoyl]amino]-1,1-dimethylethyl]sulfanyl]acetate TESTS (valyl-valneumulin), Appearance of solution.Thesolutionisclear(2.2.1) and not more intensely coloured than reference solution Y5 (2.2.2, Method II). Dissolve 2.0 g in dilute sodium hydroxide solution R and dilute to10mLwiththesamealkalinesolution. D. (2R)-2-amino-3-methylbutanoic acid (D-valine), Related substances.Gaschromatography(2.2.28). Internal standard solution.Dissolve10mgofbutyric acid R in heptane R anddiluteto200mLwiththesamesolvent. Test solution.Dissolve0.250gofthesubstancetobeexamined in the internal standard solution and dilute to 5.0 mL with the internal standard solution. Dilute 1.0 mL of this solution to 10.0 mL with heptane R. Reference solution. Dissolve 20 mg of the substance to be E. (3aS,4R,5S,6S,8R,9R,9aR,10R)6-ethenyl-5-hydroxy-4, examined and 20 mg of 2-(1-methylethyl)pentanoic acid CRS 6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH- (impurity C) in heptane R and dilute to 10 mL with the same cyclopenta[8]annulen-8-yl 2-hydroxyacetate (pleuromulin). solvent. Dilute 1 mL of this solution to 10 mL with heptane R. Column: 01/2008:1378 — material: wide-bore fused silica; VALPROIC ACID — size: l =30m,Ø=0.53mm; — stationary phase: macrogol 20 000 2-nitroterephthalate R Acidum valproicum (film thickness 0.5 μm). Carrier gas: helium for chromatography R. Flow rate:8mL/min. Temperature : Time Temperature C8H16O2 Mr 144.2 (min) (°C) [99-66-1] Column 0-10 130 DEFINITION 10 - 30 130 → 190 2-Propylpentanoic acid. Injection port 220 Content:99.0percentto101.0percent. Detector 220 CHARACTERS Detection:flameionisation. Appearance: colourless or very slightly yellow, clear liquid, slightly viscous. Injection:1μL. Solubility: very slightly soluble in water, miscible with ethanol System suitability: reference solution: (96 per cent) and with methylene chloride. It dissolves in dilute — resolution: minimum 3.0 between the peaks due to solutions of alkali hydroxides. impurity C and valproic acid.

3190 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 7.0 Valsartan

Limits: CHARACTERS — any impurity:foreachimpurity,notmorethantheareaof Appearance: white or almost white, hygroscopic powder. the peak due to the internal standard (0.1 per cent); Solubility: practically insoluble in water, freely soluble in — total: not more than 3 times the area of the peak due to the anhydrous ethanol, sparingly soluble in methylene chloride. internal standard (0.3 per cent); IDENTIFICATION — disregard limit: 0.1 times the area of the peak due to the internal standard (0.01 per cent). CarryouteithertestsA,BortestsA,C. Heavy metals (2.4.8): maximum 20 ppm. A. Infrared absorption spectrophotometry (2.2.24). Dissolve 2.0 g in ethanol (80 per cent V/V) R and dilute to Comparison: valsartan CRS. 20 mL with the same solvent. 12 mL of the solution complies B. Enantiomeric purity (see Tests). with test B. Prepare the reference solution using lead standard C. Specific optical rotation (2.2.7): − 64.0 to − 69.0 (anhydrous solution (2 ppm Pb) obtained by diluting lead standard solution substance). (100 ppm Pb) R with ethanol (80 per cent V/V) R. Dissolve 0.200 g in methanol R and dilute to 20.0 mL with Sulfated ash (2.4.14): maximum 0.1 per cent, determined on thesamesolvent. 1.0 g. TESTS ASSAY Enantiomeric purity. Liquid chromatography (2.2.29). Dissolve 0.100 g in 25 mL of ethanol (96 per cent) R.Add2mL Test solution.Dissolve50mgofthesubstancetobeexamined of water R.Titratewith0.1 M sodium hydroxide, determining in the mobile phase and dilute to 50.0 mL with the mobile phase. the end-point potentiometrically (2.2.20). Reference solution (a).Dissolve5mgofvalsartan for peak 1mLof0.1 M sodium hydroxide is equivalent to 14.42 mg of identification CRS (containing impurity A) in the mobile phase C8H16O2. and dilute to 5.0 mL with the mobile phase. STORAGE Reference solution (b).Dilute1.0mLofthetestsolutionto 100.0 mL with the mobile phase. In an airtight container. Column: IMPURITIES — size: l =0.25m,Ø=4.6mm; — stationary phase: silica gel OD for chiral separations R. Mobile phase: trifluoroacetic acid R, 2-propanol R, hexane R A.R=R′ = H: pentanoic acid (valeric acid), (0.1:15:85 V/V/V). Flow rate:0.8mL/min. B. R = H, R′ =CH-CH :(2RS)-2-ethylpentanoic acid, 2 3 Detection: spectrophotometer at 230 nm. ′ C. R = H, R =CH(CH3)2 :(2RS)-2-(1-methylethyl)pentanoic acid, Injection:10μL. ′ D. R = R =CH2-CH2-CH3 : 2,2-dipropylpentanoic acid, Run time: 1.5 times the retention time of valsartan. Identification of impurities:usethechromatogram supplied with valsartan for peak identification CRS and the chromatogram obtained with reference solution (a) to identify the peak due to impurity A. E.R=R′ = H: pentanamide (valeramide), Relative retention with reference to valsartan (retention ′ time = about 13 min): impurity A = about 0.6. F. R = H, R =CH2-CH2-CH3 :2-propylpentanamide, ′ System suitability: reference solution (a): G. R = R =CH2-CH2-CH3 :2,2-dipropylpentanamide, — resolution: minimum 2.0 between the peaks due to impurity A and valsartan. Limit: H.R=R′ = H: pentanenitrile (valeronitrile), — impurity A: not more than the area of the principal peak I. R = H, R′ =CH-CH -CH : 2-propylpentanenitrile, in the chromatogram obtained with reference solution (b) 2 2 3 (1.0 per cent). J. R = R′ =CH-CH -CH : 2,2-dipropylpentanenitrile. 2 2 3 Related substances. Liquid chromatography (2.2.29). 01/2010:2423 Test solution.Dissolve50mgofthesubstancetobeexamined in the mobile phase and dilute to 100.0 mL with the mobile VALSARTAN phase. Reference solution (a).Dilute1.0mLofthetestsolutionto Valsartanum 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase. Reference solution (b). Dissolve the contents of a vial of valsartan for system suitability CRS (containing impurity C) in 1.0 mL of the mobile phase. Column: — size: l = 0.125 m, Ø = 3.0 mm; — stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 μm). C24H29N5O3 Mr 435.5 Mobile phase: glacial acetic acid R, acetonitrile R1, water R [137862-53-4] (1:500:500 V/V/V). DEFINITION Flow rate:0.4mL/min. (2S)-3-Methyl-2-[pentanoyl[[2′-(1H-tetrazol-5-yl)biphenyl-4- Detection: spectrophotometer at 225 nm. yl]methyl]amino]butanoic acid. Injection:10μL. Content: 99.0 per cent to 101.0 per cent (anhydrous substance). Run time: 6 times the retention time of valsartan.

General Notices (1) apply to all monographs and other texts 3191