TIAMULIN HYDROGEN FUMARATE for VETERINARY USE Tiamulini

EUROPEAN PHARMACOPOEIA 9.0 Tiamulin hydrogen fumarate for veterinary use

01/2008:1659 – stationary phase: end-capped octadecylsilyl silica gel for corrected 6.0 chromatography R (5 μm), – temperature:30°C. Mobile phase: acetonitrile R1, ammonium carbonate buffer solution pH 10.0, methanol R1 (21:30:49 V/V/V). TIAMULIN HYDROGEN FUMARATE Flow rate:1.0mL/min. FOR VETERINARY USE Detection: spectrophotometer at 212 nm. Injection:20μL. Tiamulini hydrogenofumaras ad usum Run time: 3 times the retention time of tiamulin. veterinarium Identification of impurities:usethechromatogram supplied with tiamulin for peak identification CRS and the chromatogram obtained with reference solution (d) to identify thepeaksduetoimpuritiesBandH. Relative retention with reference to tiamulin (retention time = about 18 min): impurity G = about 0.2; impurity A = about 0.22; impurity H = about 0.23; impurityI=about0.3;impurityJ=about0.4; impurity K = about 0.45; impurity B = about 0.5; impurity L = about 0.65; impurity C = about 0.66; C32H51NO8S Mr 610 [55297-96-6] impurityF=about0.8;impurityM=about0.85; impurityD=about1.1;impurityS=about1.4; DEFINITION impurityT=about1.6;impurityE=2.4. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-Ethenyl-5-hydroxy-4,6,9,10- System suitability: reference solution (a): tetramethyl-1-oxodecahydro-3a,9-propano-3aH-cyclopenta- – baseline separation between the peaks due to tiamulin and cycloocten-8-yl [[2-(diethylamino)ethyl]sulfanyl]acetate impurity D. hydrogen (E)-butenedioate. Limits: Semi-synthetic product derived from a fermentation product. – impurities B, H: for each impurity, not more than 1.5 times Content: 96.5 per cent to 102.0 per cent (dried substance). theareaoftheprincipalpeakinthechromatogram CHARACTERS obtained with reference solution (b) (1.5 per cent), Appearance: white or light yellow, crystalline powder. – impurities A, C, D, E, F, G, I, J, K, L, M, S, T:foreach impurity, not more than the area of the principal peak in Solubility: soluble in water, freely soluble in anhydrous ethanol the chromatogram obtained with reference solution (b) and soluble in methanol. (1.0 per cent), IDENTIFICATION – any other impurity: for each impurity, not more than Infrared absorption spectrophotometry (2.2.24). 0.2 times the area of the principal peak in the chromatogram Comparison: tiamulin hydrogen fumarate CRS. obtained with reference solution (b) (0.2 per cent), – total: not more than 3 times the area of the principal peak TESTS in the chromatogram obtained with reference solution (b) pH (2.2.3): 3.1 to4.1. (3.0 per cent), Dissolve 0.5 g in carbon dioxide-free water R and dilute to – disregard limit: 0.1 times the area of the principal peak in 50 mL with the same solvent. the chromatogram obtained with reference solution (b) Related substances (0.1 per cent); disregard any peak present in reference .Liquidchromatography(2.2.29). solution (c). Ammonium carbonate buffer solution pH 10.0.Dissolve10.0g Loss on drying of ammonium carbonate R in water R,add22mLofperchloric (2.2.32): maximum0.5percent,determined acid solution R and dilute to 1000.0 mL with water R.Adjust on1.000gbydryinginanovenat105°C. to pH 10.0 with concentrated ammonia R1. ASSAY Solvent mixture: ammonium carbonate buffer solution Liquid chromatography (2.2.29) as described in the test for pH 10.0, acetonitrile R1 (50:50 V/V). related substances with the following modification. Test solution.Dissolve0.200gofthesubstancetobeexamined in the solvent mixture and dilute to 50.0 mL with the solvent Injection: test solution and reference solution (a). mixture. Calculate the percentage content of C32H51NO8Sfromthe Reference solution (a).Dissolve0.200goftiamulin hydrogen declared content of tiamulin hydrogen fumarate CRS. fumarate CRS inthesolventmixtureanddiluteto50.0mL STORAGE with the solvent mixture. Reference solution (b).Dilute1.0mLofthetestsolutionto Protected from light. 100.0 mL with the solvent mixture. IMPURITIES Reference solution (c). Dissolve 40.0 mg of fumaric acid R in Specified impurities: A, B, C, D, E, F, G, H, I, J, K, L, M, S, T. thesolventmixtureanddiluteto50.0mLwiththesolvent mixture. Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of Reference solution (d).Dissolve4mgoftiamulin for peak the tests in the monograph. They are limited by the general identification CRS (tiamulin hydrogen fumarate containing acceptance criterion for other/unspecified impurities and/or impurities B, C, D, F, H and I) in the solvent mixture and by the general monograph Substances for pharmaceutical use dilute to 1 mL with the solvent mixture. (2034). It is therefore not necessary to identify these impurities Column: for demonstration of compliance. See also 5.10. Control of – size: l = 0.15 m, Ø = 4.6 mm, impurities in substances for pharmaceutical use):N,O,P,Q,R.

General Notices (1) apply to all monographs and other texts 3777 Tiamulin hydrogen fumarate for veterinary use EUROPEAN PHARMACOPOEIA 9.0

A. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5,8-dihydroxy- 4,6,9,10-tetramethyloctahydro-3a,9-propano-3aH- H. (2E)-4-[(2RS)-2-[(3aS,4R,5S,6R,8R,9R,9aR,10R)-8-[[[[2- cyclopentacycloocten-1(4H)-one (mutilin), (diethylamino)ethyl]sulfanyl]acetyl]oxy]-5-hydroxy- 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH- cyclopentacycloocten-6-yl]-2-hydroxyethoxy]-4-oxobut-2- enoic acid (19,20-dihydroxytiamulin 20-fumarate),

B. 2-(benzylsulfanyl)-N,N-diethylethanamine,

I. (2E)-4-[[(3aS,4R,5S,6S,8R,9R,9aR,10R)-8-[[[[2- (diethylamino)ethyl]sulfanyl]acetyl]oxy]-6-ethenyl-1,5- dihydroxy-4,6,9,10-tetramethyldecahydro-3a,9-propano- C. 2,2’-(disulfane-1,2-diyl)bis(N,N-diethylethanamine), 3aH-cyclopentacycloocten-2-yl]oxy]-4-oxobut-2-enoic acid (2,3-dihydroxytiamulin 2-fumarate),

D. (3aR,4R,6S,8R,9R,9aR,10R)-6-ethenylhydroxy-4,6,9,10- tetramethyl-5-oxodecahydro-3a,9-propano-3aH- J. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy- cyclopentacycloocten-8-yl [[2-(diethylamino)ethyl]- 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH- sulfanyl]acetate, cyclopentacycloocten-8-yl acetate (mutilin 14-acetate),

E. (3aS,4R,6S,8R,9R,9aR,10R)-6-ethenyl-4,6,9,10-tetramethyl-1,5-dioxodecahydro-3a,9-propano-3aH-cyclopentacycloocten-8-yl [[2-(diethylamino)ethyl]sulfanyl]- acetate (11-oxotiamulin), K. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-8-hydroxy- 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH- cyclopentacycloocten-5-yl acetate (mutilin 11-acetate), F. impurity of unknown structure with a relative retention of about 0.8,

L. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy- G. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy- 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano- 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH- 3aH-cyclopentacycloocten-8-yl [[(4-methylphenyl)- cyclopentacycloocten-8-yl hydroxyacetate (pleuromutilin), sulfonyl]oxy]acetate (pleuromutilin 22-tosylate),

3778 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 9.0 Tianeptine sodium

S. (1RS,3aR,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-1-ethyl- 1,5-dihydroxy-4,6,9,10,12,12-hexamethyldecahydro- M. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-4,6,9,10- 3a,9-propano-3aH-cyclopentacycloocten-8-yl tetramethyl-1-oxodecahydro-3a,9-propano-3aH- [[2-(diethylamino)ethyl]sulfanyl]acetate, cyclopentacycloocten-5,8-diyl diacetate (mutilin 11,14-diacetate),

T. (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy- 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano- 3aH-cyclopentacycloocten-8-yl [[2-[[2-(diethylamino)- ethyl]sulfanyl]ethyl]sulfanyl]acetate. N. (2E)-4-[2-[[(3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl- 5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro- 01/2008:2022 3a,9-propano-3aH-cyclopentacycloocten-8-yl]oxy]- 2-oxoethoxy]-4-oxobut-2-enoic acid (pleuromutilin 22-fumarate), TIANEPTINE SODIUM Tianeptinum natricum

O. 2-(diethylamino)ethanethiol,

C21H24ClN2NaO4S Mr 458.9 [30123-17-2] DEFINITION Sodium 7-[[(11RS)-3-chloro-6-methyl-6,11-dihydrodibenzo- P. ( 3 a S,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy- [c,f][1,2]thiazepin-11-yl]amino]heptanoate S,S-dioxide. 4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH- Content: 99.0 per cent to 101.0 per cent (anhydrous substance). cyclopentacycloocten-8-yl [(phenylsulfonyl)oxy]acetate, CHARACTERS Appearance: white or yellowish powder, very hygroscopic. Solubility: freely soluble in water, in methanol and in methylene chloride. IDENTIFICATION A. Infrared absorption spectrophotometry (2.2.24). Comparison: Ph. Eur. reference spectrum of tianeptine sodium. Q. (3aS,4R,5S,6S,8R,9R,10R)-6-ethenyl-2,5-dihydroxy- B. It gives reaction (a) of sodium (2.3.1). 4,6,9,10-tetramethyl-2,3,4,5,6,7,8,9-octahydro- TESTS 3a,9-propano-3aH-cyclopentacycloocten-8-yl [[2-(diethylamino)ethyl]sulfanyl]acetate (3,4-didehydro- Impurity A.Gaschromatography(2.2.28). 2-hydroxytiamulin), Internal standard solution.Dilute1mLofethyl 5-bromovalerate R in ethanol R and dilute to 100.0 mL with thesamesolvent.Dilute1.0mLofthesolutionto250.0mL with ethanol R. Test solution. Dissolve0.1000gofthesubstancetobe examined in the internal standard solution and dilute to 2.0 mL with the same solution. Reference solution.Dissolve10.0mgoftianeptine impurity A CRS in the internal standard solution and dilute to R. N-benzyl-N,N-dibutylbutan-1-aminium, 200.0 mL with the same solution.

General Notices (1) apply to all monographs and other texts 3779