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CIMETIDINE HYDROCHLORIDE Cimetidini Hydrochloridum

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CIMETIDINE HYDROCHLORIDE Cimetidini Hydrochloridum Cimetidine hydrochloride EUROPEAN PHARMACOPOEIA 9.0 01/2017:1500 B. methyl 3-cyano-1-[2-[[(5-methyl-1H-imidazol-4-yl)- CIMETIDINE HYDROCHLORIDE methyl]sulfanyl]ethyl]carbamimidate, Cimetidini hydrochloridum C. 1-[(methylamino)[[2-[[(5-methyl-1H-imidazol-4-yl)- C10H17ClN6S Mr 288.8 methyl]sulfanyl]ethyl]amino]methylidene]urea, [70059-30-2] DEFINITION 2-Cyano-1-methyl-3-[2-[[(5-methyl-1H-imidazol-4-yl)- methyl]sulfanyl]ethyl]guanidine hydrochloride. Content: 98.5 per cent to 101.5 per cent (dried substance). D. 1-methyl-3-[2-[[(5-methyl-1H-imidazol-4-yl)- methyl]sulfanyl]ethyl]guanidine, CHARACTERS Appearance: white or almost white, crystalline powder. Solubility: freely soluble in water, sparingly soluble in anhydrous ethanol. IDENTIFICATION First identification: B, D. Second identification: A, C, D. E. 2-cyano-1-methyl-3[2-[[(5-methyl-1H-imidazol-4-yl)- methyl]sulfinyl]ethyl]guanidine, A. Ultraviolet and visible absorption spectrophotometry (2.2.25). Test solution.Dissolve70mgin0.2 M sulfuric acid and dilute to 100.0 mL with the same acid. Dilute 2.0 mL of this solution to 100.0 mL with 0.2 M sulfuric acid. Specific absorbance at the absorption maximum at 218 nm: 650 to 705. F. 2-cyano-1,3-bis[2-[[(5-methyl-1H-imidazol-4-yl)- B. Infrared absorption spectrophotometry (2.2.24). methyl]sulfanyl]ethyl]guanidine, Comparison: cimetidine hydrochloride CRS. C. Thin-layer chromatography (2.2.27). Test solution.Dissolve10mgofthesubstancetobe examined in methanol R and dilute to 10 mL with the same solvent. Reference solution.Dissolve10mgofcimetidine G. 2-cyano-1,3-dimethylguanidine, hydrochloride CRS in methanol R and dilute to 10 mL with thesamesolvent. Plate: TLC silica gel GF254 plate R. Mobile phase: concentrated ammonia R, methanol R, ethyl acetate R (15:20:65 V/V/V). Application:5μL. Development:over3/4oftheplate. Drying: in a current of cold air H. 1,1-(disulfanediyldiethylene)bis(2-cyano-3- methylguanidine), Detection: expose to iodine vapour until maximum contrast has been obtained and examine in ultraviolet light at 254 nm. Results: the principal spot in the chromatogram obtained with the test solution is similar in position and size to the principal spot in the chromatogram obtained with the reference solution. I. (5-methyl-1H-imidazol-4-yl)methanol, D.Itgivesreaction(a)ofchlorides(2.3.1). TESTS Appearance of solution.Thesolutionisclear(2.2.1)andnot more intensely coloured than reference solution Y5 (2.2.2, Method II). J. 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]- Dissolve 3.0 g in 12 mL of 1 M hydrochloric acid and dilute ethanamine. to 20 mL with water R. 2080 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 9.0 Cimetidine hydrochloride pH (2.2.3): 4.0 to5.0. Loss on drying (2.2.32): maximum1.0percent,determined Dissolve 100 mg in carbon dioxide-free water R and dilute to on1.000gbydryinginanovenat105°C. 10.0 mL with the same solvent. Sulfated ash (2.4.14): maximum 0.2 per cent, determined on Related substances.Liquidchromatography(2.2.29). 1.0 g. Test solution.Dissolve20mgofthesubstancetobeexamined ASSAY in mobile phase A and dilute to 50.0 mL with mobile phase A. Dissolve 0.200 g in a mixture of 5 mL of 0.01 M hydrochloric Reference solution (a). Dilute 1.0 mL of the test solution to acid and 50 mL of ethanol (96 per cent) R.Carryouta 100.0 mL with mobile phase A. Dilute 2.0 mL of this solution potentiometric titration (2.2.20), using 0.1 M sodium to 10.0 mL with mobile phase A. hydroxide. Read the volume added between the 2 points of Reference solution (b).Dissolvethecontentsofavialof inflexion. cimetidine for system suitability CRS (containing impurities B, C, D, E, G and H) in 1.0 mL of mobile phase A. 1mLof0.1 M sodium hydroxide is equivalent to 28.88 mg of C H ClN S. Reference solution (c).Dissolve4mgofcimetidine for peak 10 17 6 identification CRS (containing impurity F) in mobile phase A STORAGE anddiluteto10.0mLwithmobilephaseA. Protected from light. Column: – size: l = 0.25 m, Ø = 4.6 mm; IMPURITIES – stationary phase: end-capped octadecylsilyl silica gel for Specified impurities: B, C, D, E, F, G, H. chromatography R (5 μm). Other detectable impurities (the following substances would, Mobile phase A: mix 0.4 volumes of diethylamine R and if present at a sufficient level, be detected by one or other of 780 volumes of a 1.1 g/L solution of sodium hexanesulfonate R. the tests in the monograph. They are limited by the general Adjust to pH 2.8 with phosphoric acid R and add 250 volumes acceptance criterion for other/unspecified impurities and/or of methanol R2; by the general monograph Substances for pharmaceutical use Mobile phase B: methanol R2; (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of Time Mobile phase A Mobile phase B impurities in substances for pharmaceutical use):A,I,J. (min) (per cent V/V) (per cent V/V) 0 - 60 100 0 60 - 65 100 → 90 0 → 10 65 - 120 90 10 Flow rate:1.1mL/min. Detection: spectrophotometer at 220 nm. A. methyl 3-cyano-1-[2-[[(5-methyl-1H-imidazol-4-yl)- Injection:50μL. methyl]sulfanyl]ethyl]carbamimidothioate, Identification of impurities:usethechromatogram supplied with cimetidine for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to the impurities B, C, D, E, G and H; usethechromatogramsuppliedwith cimetidine for peak identification CRS and the chromatogram obtained with reference solution (c) to identify the peak due to impurity F. B. methyl 3-cyano-1-[2-[[(5-methyl-1H-imidazol-4-yl)- Relative retention with reference to cimetidine (retention methyl]sulfanyl]ethyl]carbamimidate, time = about 18 min): impurity G = about 0.2; impurityE=about0.4;impurityD=about1.5; impurity C = about 1.6; impurity B = about 2.0; impurity H = about 2.3; impurity F = about 4.6. System suitability: reference solution (b): – resolution: minimum 1.5 between the peaks due to impurities D and C. Limits: C. 1-[(methylamino)[[2-[[(5-methyl-1H-imidazol-4-yl)- – correction factors: for the calculation of content, multiply methyl]sulfanyl]ethyl]amino]methylidene]urea, the peak areas of the following impurities by the corresponding correction factor: impurity C = 2.5; impurity D = 3.3; impurity E = 0.7; impurity G = 0.6; – impurities B, C, D, E, F, G, H:foreachimpurity,notmore thantheareaoftheprincipalpeakinthechromatogram obtained with reference solution (a) (0.2 per cent); D. 1-methyl-3-[2-[[(5-methyl-1H-imidazol-4-yl)- – unspecified impurities:foreachimpurity,notmorethan methyl]sulfanyl]ethyl]guanidine, 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent); – total: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (1.0 per cent); – disregard limit: 0.25 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent). E. 2-cyano-1-methyl-3[2-[[(5-methyl-1H-imidazol-4-yl)- methyl]sulfinyl]ethyl]guanidine, General Notices (1) apply to all monographs and other texts 2081 Cinchocaine hydrochloride EUROPEAN PHARMACOPOEIA 9.0 Secondidentification:A,C,D,E. A. Dissolve 60.0 mg in 1 M hydrochloric acid and dilute to 100mLwiththesameacid.Dilute2mLofthesolutionto 100 mL with 1 M hydrochloric acid. Examined between F. 2-cyano-1,3-bis[2-[[(5-methyl-1H-imidazol-4-yl)- 220nmand350nm(2.2.25), the solution shows two methyl]-sulfanyl]ethyl]guanidine. absorption maxima, at 246 nm and 319 nm. The ratio of the absorbance measured at 246 nm to that measured at 319 nm is 2.7 to 3.0. B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with cinchocaine hydrochloride CRS.Examinethesubstances G. 2-cyano-1,3-dimethylguanidine, prepared as discs using potassium chloride R. C. Examine the chromatograms obtained in the test for related substances. The principal spot in the chromatogram obtained with test solution (b) is similar in position and size to the principal spot in the chromatogram obtained with reference solution (a). D. Dissolve 0.5 g in 5 mL of water R.Add1mLofdilute ammonia R2.Awhiteprecipitateisformed.Filter,washthe H. 1,1-(disulfanediyldiethylene)bis(2-cyano-3- precipitate with five quantities, each of 10 mL, of water R methylguanidine), and dry in a desiccator. It melts at 64 °C to 66 °C (2.2.14). E.Itgivesreaction(a)ofchlorides(2.3.1). TESTS Solution S.Dissolve5.0gincarbon dioxide-free water R prepared from distilled water R, and dilute to 50 mL with the I. (5-methyl-1H-imidazol-4-yl)methanol, same solvent. Appearance of solution.SolutionSisclear(2.2.1) and not more intensely coloured than reference solution Y6 (2.2.2, Method II). pH (2.2.3). Dilute 10 mL of solution S to 50 mL with carbon dioxide-free water R.ThepHofthesolutionis5.0to6.0. J. 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]- Related substances. Examine by thin-layer chromatography ethanamine. (2.2.27), using as the coating substance a suitable silica gel with a fluorescent indicator having an optimal intensity at 254 nm. Test solution (a).Dissolve0.20gofthesubstancetobe 01/2017:1088 examined in methanol R and dilute to 5 mL with the same solvent. Test solution (b).Dilute1mLoftestsolution(a)to10mL with methanol R. Reference solution (a).Dissolve20mgofcinchocaine CINCHOCAINE HYDROCHLORIDE hydrochloride CRS in methanol R and dilute to 5 mL with the same solvent. Cinchocaini hydrochloridum Reference solution (b). Dilute 1 mL of test solution (b) to 20 mL with methanol R.
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