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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 sensitivityof the detector so that the height of the principal peak inthe chromatogram obtained with reference solution (b) isnot less than 70 per cent of the full scale of the recorder.The test is not valid unless the resolution between thepeaks due to isotretinoin and tretinoin in the chromatogramobtained with reference solution (c) is at least 2.0. In the

chromatogram obtained with the test solution: the area ofany peak due to tretinoin is not greater than the area of theprincipal peak in the chromatogram obtained with referencesolution (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 thechromatogram obtained with reference solution (d) (0.5 percent).

Heavy metals (2.4.8). 0.5 g complies with limit test D forheavy metals (20 ppm). Prepare the standard using 1 ml oflead 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 ofacetone R. Titrate with 0.1 Mtetrabutylammonium hydroxide determining the end-pointpotentiometrically (2.2.20).

1 ml of0.1 M tetrabutylammonium hydroxide is equivalentto 30.04 mg of C20H28O2.

STORAGE

Store in an airtight container, protected from light, at atemperature not exceeding 25 C.

It is recommended that the contents of an opened container

be used as soon as possible and any unused part be protectedby an atmosphere of an inert gas.

IMPURITIES

A. tretinoin,

B. R = CO2H, R = H: (2Z,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid(9,13-di-cis-retinoic acid),

D. R = H, R = CO2H: (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid(9-cis-retinoic acid),

C. (2Z,4Z,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoic acid (11,13-di-cis-retinoicacid),

E. oxidation products of isotretinoin.

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ISOXSUPRINE HYDROCHLORIDE

Isoxsuprini hydrochloridum

C18H24ClNO3 Mr 337.8

DEFINITION

Isoxsuprine hydrochloride contains not less than 99.0 percent and not more than the equivalent of 101.0 per centof (1RS,2SR)-1-(4-hydroxyphenyl)-2-[[(1SR)-1-methyl-2-phenoxyethyl]amino]propan-1-ol hydrochloride, calculatedwith reference to the dried substance.

CHARACTERS

A white or almost white, crystalline powder, sparinglysoluble in water and in alcohol, practically insoluble inmethylene chloride.

It melts at about 205 C, with decomposition.

IDENTIFICATION

First identification : B, E.

Second identification: A, C, D, E.

A. Dissolve 50.0 mg in 0.1 M hydrochloric acidand dilute to50.0 ml with the same acid. Dilute 10.0 ml of this solutionto 100.0 ml with 0.1 M hydrochloric acid. Examined

between 230 nm and 350 nm (2.2.25), the solution showstwo absorption maxima, at 269 nm and 275 nm. Thespecific absorbance at these maxima are 71 to 74 and 70to 73, respectively. The test is not valid unless, in the testfor resolution (2.2.25), the ratio of the absorbances is atleast 1.7.

B. Examine by infrared absorption spectrophotometry(2.2.24), comparing with the spectrum obtainedwith isoxsuprine hydrochloride CRS. Examine thesubstances prepared as discs. If the spectra obtainedshow differences, dissolve 50 mg of the substance tobe examined and the reference substance separately in2 ml ofmethanol R, add 15 ml ofmethylene chloride R,evaporate to dryness and record new spectra using the

residues.C. Examine by thin-layer chromatography (2.2.27), using

silica gel G R as the coating substance.

Test solution. Dissolve 20 mg of the substance to beexamined in methanol R and dilute to 10 ml with thesame solvent.

Reference solution. Dissolve 20 mg of isoxsuprinehydrochloride CRS in methanol R and dilute to 10 mlwith the same solvent.

Apply to the plate 10 l of each solution. Develop overa path of 12 cm using a mixture of 0.25 volumes ofconcentrated ammonia R, 15 volumes ofmethanol Rand 85 volumes ofmethylene chloride R. Dry the plate

in a current of warm air and spray with a 10 g/l solutionofpotassium permanganate R. The principal spot in thechromatogram obtained with the test solution is similarin position, colour and size to the principal spot in thechromatogram obtained with the reference solution.

1848 See the information section on general monographs (cover pages)

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EUROPEAN PHARMACOPOEIA 5.0 Ispaghula husk

D. To 1 ml of solution S (see Tests) add 0.05 ml of coppersulphate solution R and 0.5 ml of strong sodiumhydroxide solution R. The solution becomes blue. Add1 ml ofether R and shake. Allow to separate. The upperlayer remains colourless.

E. 2 ml of solution S gives reaction (a) of chlorides (2.3.1).

TESTS

Solution S. Dissolve 0.50 g, with gentle heating if necessary,in carbon dioxide-free water R, cool and dilute to 50.0 mlwith the same solvent.

Appearance of solution. Solution S is clear (2.2.1) andcolourless (2.2.2, Method II).

pH (2.2.3). The pH of solution S is 4.5 to 6.0.

Optical rotation (2.2.7). The angle of optical rotation ofsolution S is 0.05 to + 0.05.

Phenones. Dissolve 10.0 mg in water R and dilute to100.0 ml with the same solvent. The absorbance (2.2.25)measured at the maximum at 310 nm is not greater than 0.10(1.0 per cent, calculated as impurity B).

Related substances. Prepare the solutions immediatelybefore use. Examine by gas chromatography (2.2.28), usinghexacosane R as the internal standard.

Internal standard solution (a). Dissolve 0.1 g ofhexacosane R in trimethylpentane R and dilute to 20 mlwith the same solvent.

Internal standard solution (b). Dilute 1 ml of internalstandard solution (a) to 50 ml with trimethylpentane R.

Test solution. To 10.0 mg of the substance to be examined,add 0.5 ml of N-trimethylsilylimidazole R. Heat to 65 Cfor 10 min. Allow to cool, then add 2.0 ml of the internalstandard solution (b) and 2.0 ml of water R. Shake. Use theupper layer.

Reference solution (a). To 10.0 mg of the substance tobe examined, add 0.5 ml of N-trimethylsilylimidazole R.Heat to 65 C for 10 min. Allow to cool, then add 2.0 ml ofthe internal standard solution (a) and 2.0 ml of water R.Shake. Dilute 1.0 ml of the upper layer to 50.0 ml withtrimethylpentane R.

Reference solution (b). To 10.0 mg of the substance tobe examined, add 0.5 ml of N-trimethylsilylimidazole R.Heat to 65 C for 10 min. Allow to cool, then add 2.0 ml oftrimethylpentane R and 2.0 ml ofwater R. Shake. Use theupper 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 gaschromatography R (125-135 m) impregnated with 3 percentm/m ofpoly(dimethyl)siloxane R,

nitrogen for chromatography R as the carrier gas at aflow rate of 30 ml/min,

a flame-ionisation detector,

maintaining the temperature of the column at 195 C for25 min, then raising the temperature at a rate of 5 C/minto 215 C and maintaining at 215 C for 10 min, andmaintaining the temperature of the injection port and thatof the detector at 225 C.

Inject 1 l of reference solution (a). The substances elute inthe following order: isoxsuprine and hexacosane. Adjust

the sensitivity of the detector so that the heights of the twoprincipal peaks are not less than 50 per cent of the fullscale of the recorder. The test is not valid unless, in thechromatogram obtained, the resolution between the peakscorresponding to isoxsuprine and hexacosane is at least 5.0.

Inject 1 l of reference solution (b). In the chromatogramobtained, verify that there is no peak with the same retentiontime as the internal standard.

Inject 1 l of the test solution and 1 l of referencesolution (a). From the chromatogram obtained withreference solution (a), calculate the ratio (R) of the area ofthe peak due to the trimethylsilyl derivative of isoxsuprineto the area of the peak due to the internal standard. From

the chromatogram obtained with the test solution, calculatethe ratio of the sum of the areas of any peaks, apart fromthe principal peak, the peak due to the internal standardand the peak due to the solvent, to the area of the peakdue to the internal standard: this ratio is not greater than

R (2.0 per cent).

Heavy metals (2.4.8). 1.0 g complies with limit test C forheavy metals (20 ppm). Prepare the standard using 2 ml oflead 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 an oven at 100-105 C.

Sulphated ash (2.4.14). Not more than 0.1 per cent,determined on 1.0 g.

ASSAY

Dissolve 0.250 g in 80 ml of alcohol R and add 1.0 ml of0.1 M hydrochloric acid. Carry out a potentiometric titration(2.2.20), using 0.1 M sodium hydroxide. Read the volumeadded between the two points of inflexion.

1 ml of0.1 M sodium hydroxide is equivalent to 33.78 mg ofC18H24ClNO3.

STORAGE

Store protected from light.

IMPURITIES

A. (1RS,2SR)-1-(4-hydroxyphenyl)-2-[[(1RS)-1-methyl-2-phenoxyethyl]amino]propan-1-ol,

B. 1-(4-hydroxyphenyl)-2-[(1-methyl-2-phenoxyethyl)ami-no]propan-1-one.

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ISPAGHULA HUSK

Plantaginis ovatae seminis tegumentum

DEFINITION

Ispaghula husk consists of the episperm and collapsedadjacent layers removed from the seeds of Plantago ovata

Forssk. (P. ispaghula Roxb.).

CHARACTERS

It has the macroscopic and microscopic characters describedunder identification tests A and B.

General Notices (1) apply to all monographs and other texts 1849