佐匹克隆标准

EUROPEAN PHARMACOPOEIA 7.0 Zopiclone B. Thin-layer chromatography (2.2.27). Test solution. Dissolve 50 mg of the substance to be examined in 5 mL of methanol R, add 0.1 mL of diethylamine R and dilute to 10 mL with methanol R. Reference solution (a). Dissolve 50 mg of zolpidem tartrate CRS in 5 mL of methanol R, add 0.1 mL of diethylamine R and dilute to 10 mL with methanol R. Reference solution (b). Dissolve 50mg of flunitrazepamCRS in 5 mL of methylene chloride R and dilute to 10 mL with the same solvent. Mix 1 mL of this solution with 1 mL of reference solution (a). Plate : TLC silica gel F254 plate R. Mobile phase : diethylamine R, cyclohexane R, ethyl acetate R (10:45:45 V/V/V). Application : 5 μL. Development : over 2/3 of the plate. Drying : in air. Detection : examine in ultraviolet light at 254 nm. System suitability : reference solution (b) : — the chromatogram shows 2 clearly separated spots. 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 reference solution (a). C. Dissolve about 0.1 g in 1 mL of methanol R heating gently. 0.1 mL of this solution gives reaction (b) of tartrates (2.3.1). TESTS Appearance of solution. The solution is clear (2.2.1) and not more intensely coloured than reference solution Y6 or BY6 (2.2.2, Method II). Prepare the solutions protected from light and carry out the test as rapidly as possible. Triturate 0.25 g with 0.125 g of tartaric acid R. Dissolve the mixture in 20 mL of water R and dilute to 25 mL with the same solvent. Related substances. Liquid chromatography (2.2.29). Test solution. Dissolve 25 mg of the substance to be examined in the mobile phase and dilute to 50.0 mL with the mobile phase. Reference solution (a). Dissolve 5 mg of zolpidem impurity A CRS in the mobile phase and dilute to 50.0 mL with the mobile phase. Reference solution (b). Dissolve 5 mg of the substance to be examined in the mobile phase and dilute to 50.0 mL with the mobile phase. To 10 mL of this solution, add 10 mL of reference solution (a). Reference solution (c). Dilute 2.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase. Column : — size : l = 0.15 m, Ø = 3.9 mm; — stationary phase : octadecylsilyl silica gel for chromatography R (4 μm). Mobile phase : mix 18 volumes of acetonitrile R, 23 volumes of methanol R and 59 volumes of a 5.6 g/L solution of phosphoric acid R adjusted to pH 5.5 with triethylamine R. Flow rate : 1.5 mL/min. Detection : spectrophotometer at 254 nm. Injection : 20 μL of the test solution and reference solutions (b) and (c). Identification of impurities : use the chromatogram obtained with reference solution (b) to identify the peak due to impurity A. Relative retention with reference to zolpidem (retention time = about 10 min) : tartaric acid = about 0.16 ; impurity A = about 0.8. System suitability : reference solution (b) : — resolution : minimum 2.0 between the peaks due to impurity A and zolpidem. Limits : — unspecified impurities : for each impurity, not more than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.10 per cent) ; — total : not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent) ; — disregard limit : 0.25 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.05 per cent) ; disregard any peak due to tartaric acid. Water (2.5.12) : maximum 3.0 per cent, determined on 0.50 g. Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.300 g in a mixture of 20 mL of anhydrous acetic acid R and 20 mL of acetic anhydride R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20). Carry out a blank titration. 1 mL of 0.1 M perchloric acid is equivalent to 38.24 mg of C42H48N6O8. STORAGE In an airtight container, protected from light. IMPURITIES 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) : A. A. N,N-dimethyl-2-[7-methyl-2-(4-methylphenyl)imidazo[1,2- a]pyridin-3-yl]acetamide. 01/2008:1060 ZOPICLONE Zopiclonum C17H17ClN6O3 Mr 388.8 [43200-80-2] DEFINITION (5RS)-6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate. Content : 98.5 per cent to 100.5 per cent. General Notices (1) apply to all monographs and other texts 3261 Zopiclone EUROPEAN PHARMACOPOEIA 7.0 CHARACTERS Appearance : white or slightly yellowish powder. Solubility : practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in acetone, practically insoluble in ethanol (96 per cent). It dissolves in dilute mineral acids. mp : about 177 °C, with decomposition. IDENTIFICATION First identification: B. Second identification: A, C. A. Ultraviolet and visible absorption spectrophotometry (2.2.25). Test solution. Dissolve 50.0 mg in a 3.5 g/L solution of hydrochloric acid R and dilute to 100.0 mL with the same solvent. Dilute 2.0 mL of this solution to 100.0 mL with a 3.5 g/L solution of hydrochloric acid R. Spectral range : 220-350 nm. Absorption maximum : at 303 nm. Specific absorbance at the absorption maximum : 340 to 380. B. Infrared absorption spectrophotometry (2.2.24). Preparation : discs. Comparison : zopiclone CRS. C. Thin-layer chromatography (2.2.27). Test solution. Dissolve 10 mg of the substance to be examined in methylene chloride R and dilute to 10 mL with the same solvent. Reference solution. Dissolve 10 mg of zopiclone CRS in methylene chloride R and dilute to 10 mL with the same solvent. Plate : TLC silica gel GF254 plate R. Mobile phase : triethylamine R, acetone R, ethyl acetate R (2:50:50 V/V/V). Application : 10 μL. Development : over a path of 15 cm. Drying : in air. Detection : 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. TESTS Solution S. Dissolve 1.0 g in dimethylformamide R and dilute to 20.0 mL with the same solvent. Appearance of solution. Solution S is not more opalescent than reference suspension II (2.2.1) and not more intensely coloured than intensity 5 of the range of reference solutions of the most appropriate colour (2.2.2, Method II). Optical rotation (2.2.7) : −0.05° to + 0.05°. Dilute 10.0 mL of solution S to 50.0 mL with dimethylformamide R. Related substances. Liquid chromatography (2.2.29). Prepare the solutions immediately before use. Test solution. Dissolve 40.0 mg of the substance to be examined in the mobile phase and dilute to 10.0 mL with the mobile phase. Reference solution (a). Dilute 3.0 mL of the test solution to 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). Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase. Reference solution (c). Dissolve 4.0 mg of zopiclone oxide CRS (impurity A) in the mobile phase and dilute to 10.0 mL with the mobile phase. To 10.0 mL of this solution, add 1.0 mL of the test solution and dilute to 100.0 mL with the mobile phase. Column : — size : l = 0.25 m, Ø = 4.6 mm; — stationary phase : octadecylsilyl silica gel for chromatography R (5 μm); — temperature : 30 °C. Mobile phase : mix 38 volumes of acetonitrile R and 62 volumes of a solution containing 8.1 g/L of sodium laurilsulfate R and 1.6 g/L of sodium dihydrogen phosphate R adjusted to pH 3.5 with a 10 per cent V/V solution of phosphoric acid R. Flow rate : 1.5 mL/min. Detection : spectrophotometer at 303 nm. Injection : 20 μL. Run time : 1.5 times the retention time of zopiclone. Retention time : zopiclone = 27 min to 31 min ; if necessary, adjust the concentration of acetonitrile in the mobile phase (increasing the concentration decreases the retention times). System suitability : reference solution (c) : — resolution : minimum 3.0 between the peaks due to impurity A and zopiclone ; if necessary, adjust the mobile phase to pH 4.0 with a 10 per cent V/V solution of phosphoric acid R. Limits : — impurities A, B, C : for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent) and not more than 2 such peaks have an area greater than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent). 2-Propanol. Gas chromatography (2.2.28). Internal standard solution. Dilute 5 mL of ethanol R1 to 100 mL with ethylene chloride R. Dilute 1 mL of this solution to 10 mL with ethylene chloride R. Test solution. Dissolve 0.25 g of the substance to be examined in ethylene chloride R, add 0.5 mL of the internal standard solution and dilute to 5.0 mL with ethylene chloride R. Reference solution. Dilute 4.5 mL of 2-propanol R to 100.0 mL with ethylene chloride R. To 1.0 mL of this solution, add 10.0 mL of the internal standard solution and dilute to 100.0 mL with ethylene chloride R. Column : — material : fused silica ; — size : l = 10 m, Ø = about 0.53 mm; — stationary phase : styrene-divinylbenzene copolymer R (film thickness 20 μm). Carrier gas : helium for chromatography R. Flow rate : 4 mL/min. Temperature : Time (min) Temperature (°C) Column 0 - 5 50 5 - 10 50 → 70 10 - 14 70 14 - 20.5 70 → 200 20.5 - 27.5 200 Injection port 150 Detector 250 Detection : flame ionisation. Injection : 1 μL. 3262 See the information section on general monographs (cover pages) EUROPEAN PHARMACOPOEIA 7.0 Zuclopenthixol decanoate Calculate the percentage content m/m of 2-propanol taking its density to be 0.785 g/mL at 20 °C. Limit : — 2-propanol : maximum 0.7 per cent m/m. 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. Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.300 g in a mixture of 10 mL of anhydrous acetic acid R and 40 mL of acetic anhydride 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 38.88 mg of C17H17ClN6O3. STORAGE Protected from light. IMPURITIES Specified impurities : A, B, C. A. (5RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3, 4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate 4-oxide (zopiclone oxide), B. R-OH and enantiomer : (7RS)-6-(5-chloropyridin-2-yl)-7- hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one, C. R-H: 6-(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyrazin-5-one. 01/2008:1707 ZUCLOPENTHIXOL DECANOATE Zuclopenthixoli decanoas C32H43ClN2O2S Mr 555.2 [64053-00-5] DEFINITION 2-[4-[3-[(9Z)-2-Chloro-9H-thioxanthen-9-ylidene]propyl]- piperazin-1-yl]ethyl decanoate. Content : 98.0 per cent to 102.0 per cent (dried substance). CHARACTERS Appearance : yellow, viscous, oily liquid. Solubility : very slightly soluble in water, very soluble in ethanol (96 per cent) and in methylene chloride. IDENTIFICATION Infrared absorption spectrophotometry (2.2.24). Comparison : Ph. Eur. reference spectrum of zuclopenthixol decanoate. TESTS Appearance of solution. The solution is clear (2.2.1). Using an ultrasonic bath, dissolve 1.0 g in ethanol (96 per cent) R and dilute to 20.0 mL with the same solvent. Related substances. Liquid chromatography (2.2.29). Carry out the test protected from light and prepare the solutions immediately before use. Solution A. Dissolve 8.89 g of docusate sodium R in water R, stirring for about 6-8 h, and dilute to 1000 mL with the same solvent. Test solution. Dissolve 25.0 mg of the substance to be examined in acetonitrile R and dilute to 100.0 mL with the same solvent. Reference solution (a). Dilute 1.0 mL of the test solution to 100.0 mL with acetonitrile R. Reference solution (b). Dissolve 5.0 mg of zuclopenthixol impurity B CRS in acetonitrile R and dilute to 100.0 mL with the same solvent. Dilute 5.0 mL of this solution to 100.0 mL with acetonitrile R. Reference solution (c). Dissolve the contents of a vial of zuclopenthixol for system suitability CRS (zuclopenthixol decanoate containing impurities A, B and C) in 1 mL of methanol R. Column : — size : l = 0.25 m, Ø = 4.6 mm; — stationary phase : spherical end-capped octadecylsilyl silica gel for chromatography R (5 μm); — temperature : 40 °C. Mobile phase : mix 25 volumes of solution A and 75 volumes of anhydrous ethanol R, then add 0.1 volumes of phosphoric acid R. Flow rate : 1.0 mL/min. Detection : spectrophotometer at 270 nm. Injection : 20 μL. Run time : twice the retention time of zuclopenthixol decanoate. Identification of impurities : use the chromatogram supplied with zuclopenthixol for system suitability CRS and the chromatograms obtained with reference solutions (b) and (c) to identify the peaks due to impurities A, B and C. Relative retention with reference to zuclopenthixol decanoate (retention time = about 12 min) : impurity C = about 0.4 ; impurity B = about 0.5 ; impurity A = about 1.1. System suitability : reference solution (c) : — peak-to-valley ratio : minimum 2.0, where Hp = height above the baseline of the peak due to impurity C and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to impurity B ; and minimum 2.5, where Hp = height above the baseline of the peak due to impurity A and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to zuclopenthixol decanoate. Limits : — impurity A : not more than 1.3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (1.3 per cent) ; — impurity B : not more than 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent) ; — impurity C : not more than 0.3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent) ; — unspecified impurities : for each impurity, not more than 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent) ; General Notices (1) apply to all monographs and other texts 3263 2_Volume2_E.pdf 51-Z-E toc Zolpidemi tartras TESTS Appearance of solution. The solution is clear (2.2.1) and not mo Related substances. Liquid chromatography (2.2.29). Water (2.5.12): maximum 3.0 per cent, determined on 0.50 g. Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g ASSAY STORAGE IMPURITIES Zopiclone Zopiclonum DEFINITION CHARACTERS IDENTIFICATION TESTS Solution S. Dissolve 1.0 g in dimethylformamide R and dilute to Appearance of solution. Solution S is not more opalescent than r Optical rotation (2.2.7): −0.05° to + 0.05°. Related substances. Liquid chromatography (2.2.29). Prepare the 2-Propanol. Gas chromatography (2.2.28). Heavy metals (2.4.8): maximum 20 ppm. Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g ASSAY STORAGE IMPURITIES Zuclopenthixol decanoate Zuclopenthixoli decanoas DEFINITION CHARACTERS IDENTIFICATION TESTS Appearance of solution. The solution is clear (2.2.1). Related substances. Liquid chromatography (2.2.29). Carry out th