Ketoprofen

EUROPEAN PHARMACOPOEIA 5.0

01/2005:0922 TESTS Appearance of solution. Dissolve 1.0 g in acetone R and dilute to 10 ml with the same solvent. The solution is clear KETOPROFEN (2.2.1) and not more intensely coloured than reference solution Y6 (2.2.2, Method II). Ketoprofenum Related substances. Prepare the solutions immediately before use. Examine by liquid chromatography (2.2.29). Test solution. Dissolve 20.0 mg of the substance to be examined in the mobile phase and dilute to 20.0 ml with the mobile phase. Reference solution (a). Dilute 1.0 ml of the test solution to 50.0 ml with the mobile phase. Dilute 1.0 ml to 10.0 ml with the mobile phase. Reference solution (b). Dissolve 5.0 mg of ketoprofen impurity A CRS in the mobile phase and dilute to 50.0 ml with the mobile phase. Dilute 1.0 ml to 50.0 ml with the C16H14O3 Mr 254.3 mobile phase. Reference solution (c). Dissolve 5.0 mg of ketoprofen DEFINITION impurity C CRS in the mobile phase and dilute to 50.0 ml Ketoprofen contains not less than 99.0 per cent and with the mobile phase. Dilute 1.0 ml to 50.0 ml with the not more than the equivalent of 100.5 per cent of mobile phase. (2RS)-2-(3-benzoylphenyl)propanoic acid, calculated with Reference solution (d). Dilute 1.0 ml of the test solution to reference to the dried substance. 100.0 ml with the mobile phase. To 1.0 ml add 1.0 ml of reference solution (b). CHARACTERS The chromatographic procedure may be carried out using : A white or almost white, crystalline powder, practically a stainless steel column 0.15 m long and 4.6 mm in insoluble in water, freely soluble in acetone, in ethanol internal diameter packed with a spherical octadecylsilyl (96 per cent) and in methylene chloride. silica gel for chromatography R (5 m) with a specific surface area of 350 m2/g and a pore size of 10 nm, IDENTIFICATION as mobile phase at a flow rate of 1 ml/min a mixture of First identification : C. 2 volumes of phosphate buffer solution pH 3.5 R, freshly Second identification : A, B, D. prepared, 43 volumes of acetonitrile R and 55 volumes of water R, A. Melting point (2.2.14) : 94 C to 97 C. as detector a spectrophotometer set at 233 nm, B. Dissolve 50.0 mg in ethanol (96 per cent) R and dilute to 100.0 ml with the same solvent. Dilute 1.0 ml to 50.0 ml a loop injector. with ethanol (96 per cent) R. Examined between 230 nm Inject 20 l of reference solution (d). The substances are eluted in the following order : ketoprofen and ketoprofen and 350 nm (2.2.25), the solution shows an absorption impurity A. Adjust the sensitivity of the detector so that maximum at 255 nm. The specific absorbance at the the heights of the 2 principal peaks in the chromatogram absorption maximum is 615 to 680. obtained are not less than 50 per cent of the full scale of the C. Examine by infrared absorption spectrophotometry recorder. The test is not valid unless the resolution between (2.2.24), comparing with the spectrum obtained with the peaks corresponding to ketoprofen and ketoprofen ketoprofen CRS. impurity A is at least 7.0. D. Examine by thin-layer chromatography (2.2.27), using Inject 20 l of the test solution, 20 l of reference silica gel GF254 R as the coating substance. solution (a), 20 l of reference solution (b) and 20 l of Test solution. Dissolve 10 mg of the substance to be reference solution (c). Continue the chromatography of the examined in acetone R and dilute to 10 ml with the same test solution for 7 times the retention time of ketoprofen. The solvent. relative retentions with reference to ketoprofen (retention Reference solution (a). Dissolve 10 mg of ketoprofen CRS time = about 7 min) are as follows : impurity C = about 0.34 ; impurity H = about 0.39 ; impurity G = about 0.46 ; in acetone R and dilute to 10 ml with the same solvent. impurity E = about 0.69 ; impurity B = about 0.73 ; Reference solution (b). Dissolve 10 mg of impurity D = about 1.35 ; impurity I = about 1.43 ; indometacin CRS in acetone R and dilute to 10 ml with impurity A = about 1.50 ; impurity J = about 1.86 ; the same solvent. To 1 ml of the solution add 1 ml of impurity F = about 1.95 ; impurity K = about 2.27 ; reference solution (a). impurity L = about 2.49. In the chromatogram obtained with the test solution : the areas of any peaks corresponding Apply separately to the plate 10 l of each solution. Develop over a path of 15 cm using a mixture of 1 volume to ketoprofen impurity A and ketoprofen impurity C are not greater than the areas of the principal peaks in the of glacial acetic acid R, 49 volumes of methylene chloride R and 50 volumes of acetone R. Allow the plate chromatograms obtained with reference solution (b) and reference solution (c), respectively (0.2 per cent) ; the area to dry in air and examine in ultraviolet light at 254 nm. of any peak, apart from the principal peak and any peaks The principal spot in the chromatogram obtained with corresponding to ketoprofen impurity A and ketoprofen the test solution is similar in position and size to the impurity C, is not greater than the area of the principal peak principal spot in the chromatogram obtained with in the chromatogram obtained with reference solution (a) reference solution (a). The test is not valid unless the chromatogram obtained with reference solution (b) shows (0.2 per cent) ; the sum of the areas of all the peaks, apart from the principal peak and any peaks corresponding to the 2 clearly separated principal spots. 1874 See the information section on general monographs (cover pages)

EUROPEAN PHARMACOPOEIA 5.0

Ketotifen hydrogen fumarate

2 named impurities, is not greater than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.4 per cent). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (a). Heavy metals (2.4.8). 2.0 g complies with limit test C for heavy metals (10 ppm). Prepare the reference solution using G. R = CH3, R = OH : 3-[(1RS)-1-cyanoethyl]benzoic acid, 2 ml of lead standard solution (10 ppm Pb) R. H. R = H, R = OH : 3-(cyanomethyl)benzoic acid, Loss on drying (2.2.32). Not more than 0.5 per cent, determined on 1.000 g at 60 C at a pressure not exceeding I. R = H, R = C6H5 : (3-benzoylphenyl)ethanenitrile, 670 Pa. Sulphated ash (2.4.14). Not more than 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.200 g in 25 ml of ethanol (96 per cent) R. Add 25 ml of water R. Titrate with 0.1 M sodium hydroxide, determining the end-point potentiometrically (2.2.20). 1 ml of 0.1 M sodium hydroxide is equivalent to 25.43 mg of C16H14O3. IMPURITIES Specified impurities : A, B, C, D, E, F. Other detectable impurities : G, H, I, J, K, L. J. R2 = CH3, R3 = R5 = H : (2RS)-2-[3-(2,4dimethylbenzoyl)phenyl]propanoic acid, K. R2 = R3 = CH3, R5 = H + R2 = H, R3 = R5 = CH3 : mixture of (2RS)-2-[3-(2,3,4-trimethylbenzoyl)phenyl]propanoic acid and (2RS)-2-[3-(3,4,5-trimethylbenzoyl)phenyl]propanoic acid, L. R2 = R5 = CH3, R3 = H : (2RS)-2-[3-(2,4,5trimethylbenzoyl)phenyl]propanoic acid. 01/2005:1592

KETOTIFEN HYDROGEN FUMARATE

A. 1-(3-benzoylphenyl)ethanone,

Ketotifeni hydrogenofumaras

B. R = H, R = C6H5 : (3-benzoylphenyl)acetic acid, C. R = CH3, R = OH : 3-[(1RS)-1-carboxyethyl]benzoic acid,

C23H23NO5S

Mr 425.5

DEFINITION 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10Hbenzo[4,5]cyclohepta[1,2-b]thiophen-10-one hydrogen (E)-butenedioate. Content : 98.5 per cent to 101.0 per cent (dried substance). CHARACTERS Appearance : white to brownish-yellow, fine, crystalline powder. Solubility : sparingly soluble in water, slightly soluble in methanol, very slightly soluble in acetonitrile.

D. R = CO2H, R = CH3 : (2RS)-2-[3-(4-methylbenzoyl)phenyl]propanoic acid, E. R = CO-NH2, R = H : (2RS)-2-(3-benzoylphenyl)propanamide, F. R = CN, R = H : (2RS)-2-(3-benzoylphenyl)propanenitrile, General Notices (1) apply to all monographs and other texts

IDENTIFICATION A. Infrared absorption spectrophotometry (2.2.24). Comparison : Ph. Eur. reference spectrum of ketotifen hydrogen fumarate. B. Thin-layer chromatography (2.2.27). Test solution. Dissolve 40 mg of the substance to be examined in methanol R and dilute to 10 ml with the same solvent. 1875