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EUROPEAN PHARMACOPOEIA 5.

Cyproheptadine hydrochloride

of dilute nitric acid R, 10.0 ml of 0.1 M silver nitrate and 2.0 ml of ferric ammonium sulfate solution R2 and titrate with 0.1 M ammonium thiocyanate. 1 ml of 0.1 M silver nitrate is equivalent to 13.05 mg of C7H15Cl2N2O2P.

Apply to the plate 2 l of each solution. Develop over a path of 15 cm using a mixture of 5 volumes of diethylamine R, 20 volumes of ether R and 75 volumes of cyclohexane R. Allow the plate to dry in air and examine in ultraviolet light at 254 nm. 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). The test is not valid unless the chromatogram obtained with 01/2005:0817 reference solution (b) shows 2 clearly separated principal spots. CYPROHEPTADINE D. A saturated solution gives reaction (b) of chlorides (2.3.1).

HYDROCHLORIDE

Cyproheptadini hydrochloridum

TESTS Acidity. Dissolve 0.10 g in water R and dilute to 25 ml with the same solvent. Add 0.1 ml of methyl red solution R. Not more than 0.15 ml of 0.01 M sodium hydroxide is required to change the colour of the indicator. Related substances. Examine by thin-layer chromatography (2.2.27), using silica gel G R as the coating substance. Test solution. Dissolve 50 mg of the substance to be examined in a mixture of 1 volume of methanol R and 9 volumes of methylene chloride R and dilute to 5 ml with the same mixture of solvents. Reference solution (a). Dissolve 10 mg of dibenzocycloheptene CRS (5H-dibenzo[a,d]cycloheptene) in a mixture of 1 volume of methanol R and 9 volumes of methylene chloride R and dilute to 50 ml with the same mixture of solvents. Dilute 1 ml to 10 ml with a mixture of 1 volume of methanol R and 9 volumes of methylene chloride R. Reference solution (b). Dilute 1 ml of the test solution to 100 ml with a mixture of 1 volume of methanol R and 9 volumes of methylene chloride R. Dilute 1 ml to 10 ml with a mixture of 1 volume of methanol R and 9 volumes of methylene chloride R. Apply to the plate 10 l of each solution. Develop over a path of 15 cm using a mixture of 10 volumes of methanol R and 90 volumes of methylene chloride R. Allow the plate to dry in air and spray with alcoholic solution of sulphuric acid R. Heat at 110 C for 30 min and examine in ultraviolet light at 365 nm while hot. In the chromatogram obtained with the test solution: any spot corresponding to dibenzocycloheptene is not more intense than the spot in the chromatogram obtained with reference solution (a) (0.2 per cent); any spot apart from the principal spot and any spot corresponding to dibenzocycloheptene is not more intense than the spot in the chromatogram obtained with reference solution (b) (0.1 per cent). Water (2.5.12) : 7.0 per cent to 9.0 per cent, determined on 0.200 g. Sulphated ash (2.4.14). Not more than 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.250 g in a mixture of 5.0 ml of 0.01 M hydrochloric acid and 50 ml of alcohol R. Carry out a potentiometric titration (2.2.20), using 0.1 M sodium hydroxide. Read the volume added between the 2 points of inflexion. 1 ml of 0.1 M sodium hydroxide is equivalent to 32.39 mg of C21H22ClN. STORAGE Store protected from light.

C21H22ClN,11/2 H2O

Mr 350.9

DEFINITION Cyproheptadine hydrochloride contains not less than 98.5 per cent and not more than the equivalent of 101.0 per cent of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride, calculated with reference to the anhydrous substance. CHARACTERS A white or slightly yellow, crystalline powder, slightly soluble in water, freely soluble in methanol, sparingly soluble in alcohol. IDENTIFICATION First identification: B, D. Second identification: A, C, D. A. Dissolve 50.0 mg in alcohol R and dilute to 50.0 ml with the same solvent. Dilute 2.0 ml of the solution to 100.0 ml with alcohol R. Examined between 230 nm and 320 nm (2.2.25), the solution shows an absorption maximum at 286 nm. The specific absorbance at the maximum is 335 to 365, calculated with reference to the anhydrous substance. B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with cyproheptadine hydrochloride CRS. Examine the substances as mulls in liquid paraffin R. C. Examine by thin-layer chromatography (2.2.27), using silica gel GF254 R as the coating substance. Test solution. Dissolve 25 mg of the substance to be examined in methanol R and dilute to 25 ml with the same solvent. Reference solution (a). Dissolve 10 mg of cyproheptadine hydrochloride CRS in methanol R and dilute to 10 ml with the same solvent. Reference solution (b). Dissolve 10 mg of imipramine hydrochloride CRS in methanol R and dilute to 10 ml with the same solvent. Dilute 1 ml to 2 ml with reference solution (a).

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

1379

Cyproterone acetate

EUROPEAN PHARMACOPOEIA 5.0

IMPURITIES

C. To about 1 mg add 2 ml of sulphuric acid R and heat on a water-bath for 2 min. A red colour develops. Cool. Add the solution cautiously to 4 ml of water R and shake. The solution becomes violet. D. Incinerate about 30 mg with 0.3 g of anhydrous sodium carbonate R over a naked flame for about 10 min. Cool and dissolve the residue in 5 ml of dilute nitric acid R. Filter. To 1 ml of the filtrate add 1 ml of water R. The solution gives reaction (a) of chlorides (2.3.1). E. It gives the reaction of acetyl (2.3.1).

A. R = H2 : dibenzo[a,d]cycloheptene, B. R = O: 5H-dibenzo[a,d]cyclohepten-5-one (dibenzosuberone).

TESTS Specific optical rotation (2.2.7). Dissolve 0.25 g in acetone R and dilute to 25.0 ml with the same solvent. The specific 01/2005:1094 optical rotation is + 152 to + 157, calculated with reference to the dried substance. CYPROTERONE ACETATE Related substances. Examine by liquid chromatography (2.2.29). Cyproteroni acetas Test solution. Dissolve 10.0 mg of the substance to be examined in acetonitrile R and dilute to 10.0 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 mg of medroxyprogesterone acetate CRS in acetonitrile R and dilute to 50.0 ml with the same solvent. Dilute 1.0 ml of the solution to 10.0 ml with reference solution (a). C24H29ClO4 Mr 416.9 The chromatographic procedure may be carried out using: a stainless steel column 0.125 m long and 4.6 mm in DEFINITION internal diameter packed with octadecylsilyl silica gel for Cyproterone acetate contains not less than 97.0 per chromatography R (3 m), cent and not more than the equivalent of 103.0 per cent as mobile phase at a flow rate of 1.5 ml/min a mixture of 6-chloro-3,20-dioxo-1 ,2 -dihydro-3 H-cyclopropa[1, 2]pregna-1,4,6-trien-17-yl acetate, calculated with reference to of 40 volumes of acetonitrile R and 60 volumes of water R, the dried substance. as detector a spectrophotometer set at 254 nm. CHARACTERS Inject 20 l of reference solution (a) and 20 l of reference A white or almost white, crystalline powder, practically solution (b). Adjust the sensitivity of the system so that the insoluble in water, very soluble in methylene chloride, height of the principal peak in the chromatogram obtained freely with reference solution (a) is at least 50 per cent of the full soluble in acetone, soluble in methanol, sparingly soluble scale of the recorder. The test is not valid unless, in the in ethanol. chromatogram obtained with reference solution (b), the resolution between the peak corresponding to cyproterone It melts at about 210 C. acetate and the peak corresponding to medroxyprogesterone IDENTIFICATION acetate is at least 3.0. First identification: A. Inject 20 l of the test solution. Continue the chromatography Second identification: B, C, D, E. for twice the retention time of cyproterone acetate. In the chromatogram obtained with the test solution, the sum of A. Examine by infrared absorption spectrophotometry the areas of all the peaks, apart from the principal peak, is (2.2.24), comparing with the spectrum obtained with not greater than 0.5 times the area of the principal peak cyproterone acetate CRS. B. Examine by thin-layer chromatography (2.2.27), using a in the chromatogram obtained with reference solution (a) TLC silica gel F254 plate R. (0.5 per cent). Disregard any peak with an area less than Test solution. Dissolve 20 mg of the substance to be 0.05 times that of the principal peak in the examined in methylene chloride R and dilute to 10 ml chromatogram obtained with reference solution (a). with the same solvent. Loss on drying (2.2.32). Not more than 0.5 per cent, Reference solution. Dissolve 10 mg of cyproterone acetate CRS in methylene chloride R and dilute to 5 ml determined on 1.000 g by drying at 80 C at a pressure not exceeding 0.7 kPa. with the same solvent. Sulphated ash (2.4.14). Not more than 0.1 per cent, Apply to the plate 5 l of each solution. Develop over determined on 1.0 g. a path of 15 cm using a mixture of equal volumes of cyclohexane R and ethyl acetate R. Allow the plate to dry in air. Repeat the development. Allow the plate to dry in ASSAY air. Examine in ultraviolet light at 254 nm. The principal Dissolve 50.0 mg in methanol R and dilute to 50.0 ml spot in the chromatogram obtained with the test solution with the same solvent. Dilute 1.0 ml of the solution to is similar in position and size to the principal spot in the 100.0 ml with methanol R. Measure the absorbance (2.2.25) at the maximum at 282 nm. chromatogram obtained with the reference solution. Calculate the content of C24H29ClO4 taking the specific absorbance to be 414.

1380

See the information section on general monographs (cover pages)

DEFINISI Siproheptadin hidroklorida mengandung tidak kurang dari 98,5 per persen dan tidak lebih dari setara 101,0 persen dari 4 - (5H-dibenzo [a, d] cyclohepten-5-ylidene)-1-Methylpiperidine hidroklorida, dihitung dengan mengacu pada anhidrat substansi. KARAKTER Sebuah putih atau agak kuning, kristal bubuk, sedikit larut dalam air, bebas larut dalam metanol, sedikit larut dalam alkohol. IDENTIFIKASI Identifikasi Pertama: B, D. Identifikasi Kedua: A, C, D. A. Larutkan 50,0 mg dalam alkohol R dan encer menjadi 50,0 ml dengan sama pelarut. Encerkan 2,0 ml larutan ke 100,0 ml dengan alkohol R. Diperiksa antara 230 nm dan 320 nm (2.2.25), solusinya menunjukkan maksimum penyerapan pada 286 nm. Absorbansi spesifik maksimum adalah 335-365, dihitung dengan mengacu pada anhidrat substansi. B. Periksa dengan inframerah penyerapan spektrofotometri (2.2.24), membandingkan dengan spektrum yang diperoleh dengan siproheptadin hidroklorida CRS. Periksa zat seperti berdebat dalam parafin cair R. C. Periksa dengan kromatografi lapis tipis (2.2.27), menggunakan silika gel GF254 R karena bahan pelapis. Larutan uji. Larutkan 25 mg zat untuk diperiksa dalam metanol R dan encer sampai 25 ml dengan pelarut yang sama. Solusi referensi (a). Larutkan 10 mg CRS hidroklorida siproheptadin dalam metanol R dan encerkan sampai 10 ml dengan pelarut yang sama. Solusi referensi (b). Larutkan 10 mg imipramine CRS hidroklorida dalam metanol R dan encer sampai 10 ml dengan pelarut yang sama. Encerkan 1 ml sampai 2 ml dengan mengacu solusi (a). Terapkan untuk pelat 2 ml setiap solusi . mengembangkan atas jalan 15 cm menggunakan campuran 5 volume dietilamin R , 20 volume eter R dan 75 volume sikloheksana R. Biarkan piring kering di udara dan memeriksa dalam sinar ultraviolet pada 254 nm . Kepala sekolah tempat dalam kromatogram yang diperoleh dengan larutan uji adalah serupa dalam posisi dan ukuran ke tempat utama dalam kromatogram yang diperoleh dengan larutan referensi ( a) . itu tes tidak sah kecuali kromatogram yang diperoleh dengan solusi referensi ( b ) menunjukkan 2 pokok jelas terpisah bintik-bintik . D. Sebuah solusi jenuh memberikan reaksi ( b ) klorida ( 2.3.1 ) . TES Keasaman . Larutkan 0,10 g dalam air R dan encer sampai 25 ml dengan pelarut yang sama . Tambahkan 0,1 ml metil merah solusi R. Tidak lebih dari 0,15 ml 0,01 M natrium hidroksida yang diperlukan untuk mengubah warna indikator . Zat terkait . Periksa dengan kromatografi lapis tipis ( 2.2.27 ) , menggunakan silika gel GR karena bahan pelapis . Larutan uji . Larutkan 50 mg zat yang akan diperiksa dalam campuran 1 volume metanol R dan 9 volume metilen klorida R dan encer sampai 5 ml dengan campuran pelarut yang sama . Solusi referensi ( a) . Larutkan 10 mg dibenzocycloheptene CRS ( 5H - dibenzo [a , d ] cycloheptene ) dalam campuran 1 volume metanol R dan 9 volume

metilen klorida R dan encer sampai 50 ml dengan sama campuran pelarut . Encerkan 1 ml sampai 10 ml dengan campuran dari 1 volume metanol R dan 9 volume metilen klorida R. Solusi referensi ( b ) . Encerkan 1 ml larutan uji sampai 100 ml dengan campuran 1 volume metanol R dan 9 volume metilen klorida R. Encerkan 1 ml sampai 10 ml dengan campuran 1 volume metanol R dan 9 volume metilen klorida R. Terapkan untuk pelat 10 ml dari setiap solusi . Mengembangkan atas jalan 15 cm menggunakan campuran 10 volume metanol R dan 90 volume metilen klorida R. Biarkan piring kering di udara dan semprot dengan larutan alkohol asam sulfat R. Panas pada 110 C selama 30 menit dan memeriksa di sinar ultraviolet pada 365 nm selagi panas . Dalam kromatogram diperoleh dengan larutan uji : setiap tempat sesuai dengan dibenzocycloheptene tidak lebih intens daripada tempat di kromatogram yang diperoleh dengan larutan referensi ( a) ( 0.2 per persen ) ; setiap tempat terpisah dari titik pokok dan setiap tempat sesuai dengan dibenzocycloheptene tidak lebih intens dari tempat di kromatogram yang diperoleh dengan mengacu solusi ( b ) ( 0,1 persen ) . Air ( 2.5.12 ) : 7,0 persen menjadi 9,0 persen , ditentukan 0.200 g . Sulfat ash ( 2.4.14 ) . Tidak lebih dari 0,1 persen , ditentukan 1,0 g . UJI Larutkan 0.250 g dalam campuran 5.0 ml 0,01 M asam klorida dan 50 ml alkohol R. Melaksanakan potensiometri titrasi ( 2.2.20 ) , menggunakan 0,1 M natrium hidroksida . Baca volume ditambahkan antara 2 titik infleksi . 1 ml 0,1 M natrium hidroksida setara dengan 32,39 mg C21H22ClN . PENYIMPANAN Simpan terlindung dari cahaya .