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Isoxsuprine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

Inject separately 10 l of each of reference solutions (b), (c) and (d) and of the test solution. Adjust the sensitivity of the detector so that the height of the principal peak in the chromatogram obtained with reference solution (b) is not less than 70 per cent of the full scale of the recorder. The test is not valid unless the resolution between the peaks due to isotretinoin and tretinoin in the chromatogram obtained with reference solution (c) is at least 2.0. In the chromatogram obtained with the test solution : the area of any peak due to tretinoin is not greater than the area of the principal peak in the chromatogram obtained with reference solution (b) (2.0 per cent) ; the sum of the areas of any peaks, apart from the principal peak and any peak due to tretinoin, is not greater than the area of the principal peak in the chromatogram obtained with reference solution (d) (0.5 per cent). Heavy metals (2.4.8). 0.5 g complies with limit test D for heavy metals (20 ppm). Prepare the standard using 1 ml of lead standard solution (10 ppm Pb) R. Loss on drying (2.2.32). Not more than 0.5 per cent, determined on 1.000 g by drying in vacuo for 16 h. Sulphated ash (2.4.14). Not more than 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.200 g in 70 ml of acetone R. Titrate with 0.1 M tetrabutylammonium hydroxide determining the end-point potentiometrically (2.2.20). 1 ml of 0.1 M tetrabutylammonium hydroxide is equivalent to 30.04 mg of C20H28O2.

01/2005:1119

ISOXSUPRINE HYDROCHLORIDE Isoxsuprini hydrochloridum

C18H24ClNO3

Mr 337.8

DEFINITION Isoxsuprine hydrochloride contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of (1RS,2SR)-1-(4-hydroxyphenyl)-2-[[(1SR)-1-methyl-2phenoxyethyl]amino]propan-1-ol hydrochloride, calculated with reference to the dried substance. CHARACTERS A white or almost white, crystalline powder, sparingly soluble in water and in alcohol, practically insoluble in methylene chloride. It melts at about 205 C, with decomposition.

IDENTIFICATION First identification : B, E. Second identification : A, C, D, E. STORAGE A. Dissolve 50.0 mg in 0.1 M hydrochloric acid and dilute to Store in an airtight container, protected from light, at a 50.0 ml with the same acid. Dilute 10.0 ml of this solution temperature not exceeding 25 C. to 100.0 ml with 0.1 M hydrochloric acid. Examined It is recommended that the contents of an opened container between 230 nm and 350 nm (2.2.25), the solution shows be used as soon as possible and any unused part be protected two absorption maxima, at 269 nm and 275 nm. The by an atmosphere of an inert gas. specific absorbance at these maxima are 71 to 74 and 70 to 73, respectively. The test is not valid unless, in the test IMPURITIES for resolution (2.2.25), the ratio of the absorbances is at A. tretinoin, least 1.7. B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with isoxsuprine hydrochloride CRS. Examine the substances prepared as discs. If the spectra obtained show differences, dissolve 50 mg of the substance to be examined and the reference substance separately in 2 ml of methanol R, add 15 ml of methylene chloride R, evaporate to dryness and record new spectra using the residues. C. Examine by thin-layer chromatography (2.2.27), using B. R = CO2H, R = H : (2Z,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6silica gel G R as the coating substance. trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid (9,13-di-cis-retinoic acid), Test solution. Dissolve 20 mg of the substance to be examined in methanol R and dilute to 10 ml with the D. R = H, R = CO2H : (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6, same solvent. 6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid Reference solution. Dissolve 20 mg of isoxsuprine (9-cis-retinoic acid), hydrochloride CRS in methanol R and dilute to 10 ml with the same solvent. Apply to the plate 10 l of each solution. Develop over a path of 12 cm using a mixture of 0.25 volumes of concentrated ammonia R, 15 volumes of methanol R and 85 volumes of methylene chloride R. Dry the plate in a current of warm air and spray with a 10 g/l solution C. (2Z,4Z,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexof potassium permanganate R. The principal spot in the 1-enyl)nona-2,4,6,8-tetraenoic acid (11,13-di-cis-retinoic chromatogram obtained with the test solution is similar acid), in position, colour and size to the principal spot in the chromatogram obtained with the reference solution. E. oxidation products of isotretinoin. 1848 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 5.0

Ispaghula husk

Inject 1 l of reference solution (b). In the chromatogram obtained, verify that there is no peak with the same retention time as the internal standard. Inject 1 l of the test solution and 1 l of reference solution (a). From the chromatogram obtained with reference solution (a), calculate the ratio (R) of the area of the peak due to the trimethylsilyl derivative of isoxsuprine TESTS to the area of the peak due to the internal standard. From Solution S. Dissolve 0.50 g, with gentle heating if necessary, the chromatogram obtained with the test solution, calculate the ratio of the sum of the areas of any peaks, apart from in carbon dioxide-free water R, cool and dilute to 50.0 ml the principal peak, the peak due to the internal standard with the same solvent. and the peak due to the solvent, to the area of the peak Appearance of solution. Solution S is clear (2.2.1) and due to the internal standard : this ratio is not greater than colourless (2.2.2, Method II). R (2.0 per cent). pH (2.2.3). The pH of solution S is 4.5 to 6.0. Heavy metals (2.4.8). 1.0 g complies with limit test C for Optical rotation (2.2.7). The angle of optical rotation of heavy metals (20 ppm). Prepare the standard using 2 ml of solution S is 0.05 to + 0.05. lead standard solution (10 ppm Pb) R. Phenones. Dissolve 10.0 mg in water R and dilute to Loss on drying (2.2.32). Not more than 0.5 per cent, 100.0 ml with the same solvent. The absorbance (2.2.25) determined on 1.000 g by drying in an oven at 100-105 C. measured at the maximum at 310 nm is not greater than 0.10 Sulphated ash (2.4.14). Not more than 0.1 per cent, (1.0 per cent, calculated as impurity B). determined on 1.0 g. Related substances. Prepare the solutions immediately before use. Examine by gas chromatography (2.2.28), using ASSAY Dissolve 0.250 g in 80 ml of alcohol R and add 1.0 ml of hexacosane R as the internal standard. 0.1 M hydrochloric acid. Carry out a potentiometric titration Internal standard solution (a). Dissolve 0.1 g of (2.2.20), using 0.1 M sodium hydroxide. Read the volume hexacosane R in trimethylpentane R and dilute to 20 ml added between the two points of inflexion. with the same solvent. 1 ml of 0.1 M sodium hydroxide is equivalent to 33.78 mg of Internal standard solution (b). Dilute 1 ml of internal C H ClNO 18 24 3. standard solution (a) to 50 ml with trimethylpentane R. Test solution. To 10.0 mg of the substance to be examined, STORAGE add 0.5 ml of N-trimethylsilylimidazole R. Heat to 65 C Store protected from light. for 10 min. Allow to cool, then add 2.0 ml of the internal standard solution (b) and 2.0 ml of water R. Shake. Use the IMPURITIES upper layer. Reference solution (a). To 10.0 mg of the substance to be examined, add 0.5 ml of N-trimethylsilylimidazole R. Heat to 65 C for 10 min. Allow to cool, then add 2.0 ml of the internal standard solution (a) and 2.0 ml of water R. Shake. Dilute 1.0 ml of the upper layer to 50.0 ml with trimethylpentane R. A. (1RS,2SR)-1-(4-hydroxyphenyl)-2-[[(1RS)-1-methyl-2Reference solution (b). To 10.0 mg of the substance to phenoxyethyl]amino]propan-1-ol, be examined, add 0.5 ml of N-trimethylsilylimidazole R. Heat to 65 C for 10 min. Allow to cool, then add 2.0 ml of trimethylpentane R and 2.0 ml of water R. Shake. Use the upper layer. The chromatographic procedure may be carried out using : a glass column 1.5 m long and 4 mm in internal diameter, packed with silanised diatomaceous earth for gas B. 1-(4-hydroxyphenyl)-2-[(1-methyl-2-phenoxyethyl)amichromatography R (125-135 m) impregnated with 3 per no]propan-1-one. cent m/m of poly(dimethyl)siloxane R, nitrogen for chromatography R as the carrier gas at a flow rate of 30 ml/min, 01/2005:1334 a flame-ionisation detector, maintaining the temperature of the column at 195 C for ISPAGHULA HUSK 25 min, then raising the temperature at a rate of 5 C/min to 215 C and maintaining at 215 C for 10 min, and Plantaginis ovatae seminis tegumentum maintaining the temperature of the injection port and that of the detector at 225 C. DEFINITION Inject 1 l of reference solution (a). The substances elute in Ispaghula husk consists of the episperm and collapsed the following order : isoxsuprine and hexacosane. Adjust adjacent layers removed from the seeds of Plantago ovata the sensitivity of the detector so that the heights of the two Forssk. (P. ispaghula Roxb.). principal peaks are not less than 50 per cent of the full CHARACTERS scale of the recorder. The test is not valid unless, in the chromatogram obtained, the resolution between the peaks It has the macroscopic and microscopic characters described corresponding to isoxsuprine and hexacosane is at least 5.0. under identification tests A and B. D. To 1 ml of solution S (see Tests) add 0.05 ml of copper sulphate solution R and 0.5 ml of strong sodium hydroxide solution R. The solution becomes blue. Add 1 ml of ether R and shake. Allow to separate. The upper layer remains colourless. E. 2 ml of solution S gives reaction (a) of chlorides (2.3.1). General Notices (1) apply to all monographs and other texts 1849