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EUROPEAN PHARMACOPOEIA 5.0 Cyproheptadine hydrochloride

ofdilute nitric acid R, 10.0 ml of0.1 M silver nitrate and2.0 ml offerric ammonium sulfate solution R2and titratewith 0.1 M ammonium thiocyanate.

1 ml of0.1 M silver nitrate is equivalent to 13.05 mg ofC7H15Cl2N2O2P.

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CYPROHEPTADINEHYDROCHLORIDE

Cyproheptadini hydrochloridum

C21H22ClN,11/2 H2O Mr350.9

DEFINITION

Cyproheptadine hydrochloride contains not less than 98.5 percent and not more than the equivalent of 101.0 per cent of4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidinehydrochloride, calculated with reference to the anhydroussubstance.

CHARACTERS

A white or slightly yellow, crystalline powder, slightlysoluble in water, freely soluble in methanol, sparinglysoluble inalcohol.

IDENTIFICATION

First identification: B, D.

Second identification: A, C, D.

A. Dissolve 50.0 mg in alcohol Rand dilute to 50.0 ml withthe same solvent. Dilute 2.0 ml of the solution to 100.0 mlwith alcohol R. Examined between 230 nm and 320 nm(2.2.25), the solution shows an absorption maximumat 286 nm. The specific absorbance at the maximum is

335 to 365, calculated with reference to the anhydroussubstance.

B. Examine by infrared absorption spectrophotometry(2.2.24), comparing with the spectrum obtained withcyproheptadine hydrochloride CRS. Examine thesubstances as mulls in liquid paraffin R.

C. Examine by thin-layer chromatography (2.2.27), usingsilica gel GF254 Ras the coating substance.

Test solution. Dissolve 25 mg of the substance to beexamined in methanol Rand dilute to 25 ml with thesame solvent.

Reference solution (a). Dissolve 10 mg ofcyproheptadinehydrochloride CRS in methanol Rand dilute to 10 ml

with the same solvent.

Reference solution (b). Dissolve 10 mg of imipraminehydrochloride CRS in methanol Rand dilute to 10 mlwith the same solvent. Dilute 1 ml to 2 ml with referencesolution (a).

Apply to the plate 2 l of each solution. Developover a path of 15 cm using a mixture of 5 volumes ofdiethylamine R, 20 volumes ofether Rand 75 volumesofcyclohexane R. Allow the plate to dry in air andexamine in ultraviolet light at 254 nm. The principal spotin the chromatogram obtained with the test solution issimilar in position and size to the principal spot in thechromatogram obtained with reference solution (a). The

test is not valid unless the chromatogram obtained withreference solution (b) shows 2 clearly separated principalspots.

D. A saturated solution gives reaction (b) of chlorides (2.3.1).

TESTS

Acidity. Dissolve 0.10 g in water Rand dilute to 25 mlwith the same solvent. Add 0.1 ml ofmethyl red solutionR. Not more than 0.15 ml of0.01 M sodium hydroxide isrequired to change the colour of the indicator.

Related substances. Examine by thin-layer chromatography(2.2.27), using silica gel G Ras the coating substance.

Test solution. Dissolve 50 mg of the substance to beexamined in a mixture of 1 volume of methanol Rand9 volumes ofmethylene chloride Rand dilute to 5 ml withthe same mixture of solvents.

Reference solution (a). Dissolve 10 mg ofdibenzocycloheptene CRS (5H-dibenzo[a,d]cycloheptene)in a mixture of 1 volume ofmethanol Rand 9 volumesofmethylene chloride Rand dilute to 50 ml with the samemixture of solvents. Dilute 1 ml to 10 ml with a mixtureof 1 volume ofmethanol Rand 9 volumes ofmethylenechloride R.

Reference solution (b). Dilute 1 ml of the test solution

to 100 ml with a mixture of 1 volume ofmethanol Rand9 volumes ofmethylene chloride R. Dilute 1 ml to 10 mlwith a mixture of 1 volume ofmethanol Rand 9 volumesofmethylene chloride R.

Apply to the plate 10 l of each solution. Develop over apath of 15 cm using a mixture of 10 volumes ofmethanol Rand 90 volumes ofmethylene chloride R. Allow theplate to dry in air and spray with alcoholic solution ofsulphuric acid R. Heat at 110 C for 30 min and examine inultraviolet light at 365 nm while hot. In the chromatogramobtained with the test solution: any spot corresponding todibenzocycloheptene is not more intense than the spot in thechromatogram obtained with reference solution (a) (0.2 percent); any spot apart from the principal spot and any spot

corresponding to dibenzocycloheptene is not more intensethan the spot in the chromatogram obtained with referencesolution (b) (0.1 per cent).

Water(2.5.12) : 7.0 per cent to 9.0 per cent, determined on0.200 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 of0.01 M hydrochloricacidand 50 ml ofalcohol R. Carry out a potentiometrictitration (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 32.39mg of C21H22ClN.

STORAGE

Store protected from light.

General Notices (1) apply to all monographs and other texts 1379

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Cyproterone acetate EUROPEAN PHARMACOPOEIA 5.0

IMPURITIES

A. R = H2 : dibenzo[a,d]cycloheptene,

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

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CYPROTERONE ACETATE

Cyproteroni acetas

C24H29ClO4 Mr 416.9

DEFINITION

Cyproterone acetate contains not less than 97.0 percent and not more than the equivalent of 103.0 per centof 6-chloro-3,20-dioxo-1 ,2 -dihydro-3 H-cyclopropa[1,

2]pregna-1,4,6-trien-17-yl acetate, calculated with referencetothe dried substance.

CHARACTERS

A white or almost white, crystalline powder, practicallyinsoluble in water, very soluble in methylene chloride,freelysoluble in acetone, soluble in methanol, sparingly solublein ethanol.

It melts at about 210 C.

IDENTIFICATION

First identification: A.

Second identification: B, C, D, E.

A. Examine by infrared absorption spectrophotometry(2.2.24), comparing with the spectrum obtained withcyproterone acetate CRS.

B. Examine by thin-layer chromatography (2.2.27), using aTLC silica gel F254 plate R.

Test solution. Dissolve 20 mg of the substance to beexamined in methylene chloride Rand dilute to 10 mlwith the same solvent.

Reference solution. Dissolve 10 mg ofcyproteroneacetate CRS in methylene chloride Rand dilute to 5 mlwith the same solvent.

Apply to the plate 5 l of each solution. Develop overa path of 15 cm using a mixture of equal volumes of

cyclohexane Rand ethyl acetate R. Allow the plate to dryin air. Repeat the development. Allow the plate to dry inair. Examine in ultraviolet light at 254 nm. The principalspot in the chromatogram obtained with the test solutionis similar in position and size to the principal spot in thechromatogram obtained with the reference solution.

C. To about 1 mg add 2 ml ofsulphuric acid Rand heaton a water-bath for 2 min. A red colour develops. Cool.

Add the solution cautiously to 4 ml ofwater Rand shake.The solution becomes violet.

D. Incinerate about 30 mg with 0.3 g ofanhydrous sodiumcarbonate Rover a naked flame for about 10 min. Cooland dissolve the residue in 5 ml ofdilute nitric acid R.Filter. To 1 ml of the filtrate add 1 ml ofwater R. The

solution gives reaction (a) of chlorides (2.3.1).E. It gives the reaction of acetyl (2.3.1).

TESTS

Specific optical rotation (2.2.7). Dissolve 0.25 g in acetoneRand dilute to 25.0 ml with the same solvent. The specificoptical rotation is + 152 to + 157, calculated with referenceto the dried substance.

Related substances. Examine by liquid chromatography(2.2.29).

Test solution. Dissolve 10.0 mg of the substance to beexamined in acetonitrile Rand dilute to 10.0 ml with thesame solvent.

Reference solution (a). Dilute 1.0 ml of the test solution to100.0 ml with acetonitrile R.

Reference solution (b). Dissolve 5 mg ofmedroxyprogesterone acetate CRS in acetonitrile Rand dilute to 50.0 ml with the same solvent. Dilute 1.0 mlofthe solution to 10.0 ml with reference solution (a).The chromatographic procedure may be carried out using: a stainless steel column 0.125 m long and 4.6 mm in

internal diameter packed with octadecylsilyl silica gel forchromatography R(3 m),

as mobile phase at a flow rate of 1.5 ml/min a mixture

of

40 volumes ofacetonitrile Rand 60 volumes ofwater R, as detector a spectrophotometer set at 254 nm.

Inject 20 l of reference solution (a) and 20 l of referencesolution (b). Adjust the sensitivity of the system so that theheight of the principal peak in the chromatogram obtainedwith reference solution (a) is at least 50 per cent of the fullscale of the recorder. The test is not valid unless, in thechromatogram obtained with reference solution (b), theresolution between the peak corresponding to cyproteroneacetate and the peak corresponding to medroxyprogesteroneacetate is at least 3.0.

Inject 20 l of the test solution. Continue the chromatographyfor twice the retention time of cyproterone acetate. In the

chromatogram obtained with the test solution, the sum ofthe areas of all the peaks, apart from the principal peak, isnot greater than 0.5 times the area of the principal peakin the chromatogram obtained with reference solution(a)(0.5 per cent). Disregard any peak with an area less than0.05 times that of the principal peak in thechromatogram obtained with reference solution (a).

Loss on drying (2.2.32). Not more than 0.5 per cent,determined on 1.000 g by drying at 80 C at a pressure notexceeding 0.7 kPa.

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

ASSAY

Dissolve 50.0 mg in methanol R and dilute to 50.0 mlwith the same solvent. Dilute 1.0 ml of the solution to100.0 ml with methanol R. Measure the absorbance(2.2.25) at the maximum at 282 nm.

Calculate the content of C24H29ClO4 taking thespecific absorbance to be 414.

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1380 See the information section on general monographs (cover pages)

DEFINISISiproheptadin hidroklorida mengandung tidak kurang dari 98,5 perpersen dan tidak lebih dari setara 101,0 persen dari4 - (5H-dibenzo [a, d] cyclohepten-5-ylidene)-1-Methylpiperidinehidroklorida, dihitung dengan mengacu pada anhidratsubstansi.KARAKTER

Sebuah putih atau agak kuning, kristal bubuk, sedikit larut dalam air, bebas larut dalam metanol,sedikit larut dalamalkohol.IDENTIFIKASIIdentifikasi Pertama: B, D.Identifikasi Kedua: A, C, D.A. Larutkan 50,0 mg dalam alkohol R dan encer menjadi 50,0 ml dengansama pelarut. Encerkan 2,0 ml larutan ke 100,0 mldengan alkohol R. Diperiksa antara 230 nm dan 320 nm(2.2.25), solusinya menunjukkan maksimum penyerapanpada 286 nm. Absorbansi spesifik maksimum adalah

335-365, dihitung dengan mengacu pada anhidratsubstansi.B. Periksa dengan inframerah penyerapan spektrofotometri(2.2.24), membandingkan dengan spektrum yang diperoleh dengansiproheptadin hidroklorida CRS. Periksa zat seperti berdebat dalam parafin cair R.C. Periksa dengan kromatografi lapis tipis (2.2.27), menggunakansilika gel GF254 R karena bahan pelapis.Larutan uji. Larutkan 25 mg zat untuk diperiksa dalam metanol R dan encer sampai 25 ml denganpelarut yang sama.Solusi referensi (a). Larutkan 10 mg CRS hidroklorida siproheptadin dalam metanol R dan encerkansampai 10 ml dengan pelarut yang sama.

Solusi referensi (b). Larutkan 10 mg imipramineCRS hidroklorida dalam metanol R dan encer sampai 10 mldengan pelarut yang sama. Encerkan 1 ml sampai 2 ml dengan mengacusolusi (a).

Terapkan untuk pelat 2 ml setiap solusi . mengembangkanatas jalan 15 cm menggunakan campuran 5 volumedietilamin R , 20 volume eter R dan 75 volumesikloheksana R. Biarkan piring kering di udara danmemeriksa dalam sinar ultraviolet pada 254 nm . Kepala sekolah tempatdalam kromatogram yang diperoleh dengan larutan uji adalahserupa dalam posisi dan ukuran ke tempat utama dalamkromatogram yang diperoleh dengan larutan referensi ( a) . itutes tidak sah kecuali kromatogram yang diperoleh dengansolusi referensi ( b ) menunjukkan 2 pokok jelas terpisahbintik-bintik .D. Sebuah solusi jenuh memberikan reaksi ( b ) klorida ( 2.3.1 ) .TESKeasaman . 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 yangdiperlukan untuk mengubah warna indikator .

Zat terkait . Periksa dengan kromatografi lapis tipis ( 2.2.27 ) , menggunakan silika gel GR karenabahan pelapis .Larutan uji . Larutkan 50 mg zat yang akandiperiksa dalam campuran 1 volume metanol R dan9 volume metilen klorida R dan encer sampai 5 ml dengan campuran pelarut yang sama .Solusi referensi ( a) . Larutkan 10 mgdibenzocycloheptene CRS ( 5H - dibenzo [a , d ] cycloheptene )dalam campuran 1 volume metanol R dan 9 volume

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metilen klorida R dan encer sampai 50 ml dengan samacampuran pelarut . Encerkan 1 ml sampai 10 ml dengan campurandari 1 volume metanol R dan 9 volume metilenklorida R.Solusi referensi ( b ) . Encerkan 1 ml larutan ujisampai 100 ml dengan campuran 1 volume metanol R dan9 volume metilen klorida R. Encerkan 1 ml sampai 10 ml dengan campuran 1 volume metanol Rdan 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. Biarkanpiring kering di udara dan semprot dengan larutan alkoholasam sulfat R. Panas pada 110 C selama 30 menit dan memeriksa disinar ultraviolet pada 365 nm selagi panas . Dalam kromatogramdiperoleh dengan larutan uji : setiap tempat sesuai dengandibenzocycloheptene tidak lebih intens daripada tempat dikromatogram yang diperoleh dengan larutan referensi ( a) ( 0.2 perpersen ) ; setiap tempat terpisah dari titik pokok dan setiap tempatsesuai dengan dibenzocycloheptene tidak lebih intensdari tempat di kromatogram yang diperoleh dengan mengacusolusi ( b ) ( 0,1 persen ) .

Air ( 2.5.12 ) : 7,0 persen menjadi 9,0 persen , ditentukan0.200 g .Sulfat ash ( 2.4.14 ) . Tidak lebih dari 0,1 persen , ditentukan 1,0 g .UJILarutkan 0.250 g dalam campuran 5.0 ml 0,01 M asam klorida dan 50 ml alkohol R. Melaksanakanpotensiometrititrasi ( 2.2.20 ) , menggunakan 0,1 M natrium hidroksida . Baca volume ditambahkan antara 2 titikinfleksi .1 ml 0,1 M natrium hidroksida setara dengan 32,39 mg C21H22ClN .PENYIMPANANSimpan terlindung dari cahaya .