EUROPEAN PHARMACOPOEIA 5.

Fluoxetine hydrochloride

about 2 mg of the substance to be examined and heat again in a naked flame until white fumes appear. The solution does not wet the sides of the tube. TESTS Solution S. Dissolve 0.5 g in carbon dioxide free water ! and dilute to 50 ml with the same solvent. "ppearance of solution. Solution S is clear #2.2.$% and not more intensel& coloured than reference solution '() or () #2.2.2* +ethod ,,%. p- #2.2..%. The p- of solution S is /.5 to 5.0. !elated substances. Examine b& thin la&er chromatograph& #2.2.2)%* using silica gel 0125/ ! as the coating substance. Test solution #a%. Dissolve 0.$0 g of the substance to be examined in a mixture of e2ual volumes of methanol ! and water ! and dilute to $0.0 ml with the same mixture of solvents. Test solution #b%. Dilute 2 ml of test solution #a% to $0 ml with a mixture of e2ual volumes of methanol ! and water !. !eference solution #a%. Dissolve 20 mg of fluorouracil 3!S in a mixture of e2ual volumes of methanol ! and water ! and dilute to $0 ml with the same mixture of solvents. !eference solution #b%. Dilute 2.5 ml of reference solution #a% to 200 ml with a mixture of e2ual volumes of methanol ! and water !. !eference solution #c%. Dissolve 5 mg of 5 h&drox&uracil ! in a mixture of e2ual volumes of methanol ! and water ! and dilute to 200 ml with the same mixture of solvents. "ppl& to the plate $0 pl of each solution. Develop over a path of $2 cm using a mixture of $5 volumes of methanol !* $5 volumes of water ! and )0 volumes of eth&l acetate !. "llow the plate to dr& in air and examine in ultraviolet light at 25/
General Notices (1) apply to all monographs and other texts

01/ 005!110"

F#UO$E%INE H&'ROCH#ORI'E
H

Fluoxetini hydrochloridu(

nm. "n& spot in the chromatogram obtained with test solution #a%* apart from the principal spot* is not more intense than the spot in the chromatogram obtained with reference solution #b% #0.25 per cent%. Spra& with a freshl& prepared 5 g4l solution of fast blue ' salt ! and subse2uentl& with 0.$ + sodium h&droxide. "n& spot corresponding to 5 h&drox&uracil in the chromatogram obtained with test solution #a% is not more intense than the spot in the chromatogram obtained with reference solution #c% #0.25 per cent%. -eav& metals #2./.5%. 6se a platinum crucible. $.0 g complies with limit test 3 for heav& metals #20 ppm%. 7repare the standard using 2 ml of lead standard solution #$0 ppm 7b% !. 8oss on dr&ing #2.2..2%. 9ot more than 0.5 per cent* determined on $.000 g b& dr&ing in vacuo at 50 :3 for / h. Sulphated ash #2./.$/%. 6se a platinum crucible. 9ot more than 0.$ per cent* determined on $.0 g. "SS"( Dissolve 0.$000 g in 50 ml of dimeth&lformamide !* warming gentl&. 3ool and titrate with 0.$ + tetrabut&lammonium h&droxide* using 0.25 ml of a $0 g4l solution of th&mol blue ! in dimeth&lformamide ! as indicator. 3arr& out a blank titration. $ ml of 0.$ + tetrabut&lammonium h&droxide is e2uivalent to $..0$ mg of 3/-.192;2. ST;!"0E Store protected from light. 3-.
1)15

Monographs

Fluoxetine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

and enantiomer * -3, 3$)-$<3l1.9; +r ./5.5 DE1,9,T,;9 1luoxetine h&drochloride contains not less than per cent and not more than the e2uivalent of $02.0 per cent of #.!S% 9 meth&l . phen&l . =/ #trifluorometh&l%phenox&>propan $ amine h&drochloride* calculated with reference to the anh&drous* acetonitrile free substance. 3-"!"3TE!S " white or almost white* cr&stalline powder* sparingl& soluble in water* freel& soluble in methanol* sparingl& soluble in meth&lene chloride. ,DE9T,1,3"T,;9 Examine b& infrared absorption spectrophotometr& #2.2.2/%* comparing with the spectrum obtained with fluoxetine h&drochloride 3!S. Examine the substances prepared as discs. ,t gives reaction #a% of chlorides #2...$%. TESTS Solution S. Dissolve 2.0 g in a mixture of $5 volumes of water ! and 55 volumes of methanol ! and dilute to $00 ml with the same mixture of solvents. "ppearance of solution. Solution S is clear #2.2.$% and colourless #2.2.2* +ethod ,,%. p- #2.2..%. Dissolve 0.20 g in carbon dioxide free water ! and dilute to 20 ml with the same solvent. The p- of the solution is /.5 to ?.5. ;ptical rotation #2.2.)%@ 0.05: to A 0.05:* determined on solution S. !elated substances. Examine b& li2uid chromatograph& #2.2.2<% as prescribed under "ssa&* setting the spectrophotometer at 2$5 nm. Test solution #a%. Dissolve 55.0 mg of the substance to be examined in the mobile phase and dilute to $0.0 ml with the mobile phase. Test solution #b%. Dilute 2.0 ml of test

solution #a% to $0.0 ml with the mobile phase. !eference solution. Dissolve 22.0 mg of fluoxetine h&drochloride 3!S in $0.0 ml of 0.5 + sulphuric acid. -eat at about 55 :3 for . h. "llow to cool. The resulting solution contains considerable 2uantities of impurit& " and / trifluorometh&lphenol. To 0./ ml of the solution* add 25.0 mg of fluoxetine h&drochloride 3!S and about mg of fluoxetine impurit& ' 3!S and of fluoxetine impurit& 3 3!S and dilute to 25.0 ml with the mobile phase. Bhen the chromatograms are recorded in the prescribed conditions* the retention times relative to fluoxetine are@ impurit& " about 0.2/* impurit& ' about 0.2) and impurit& 3 about 0.</. ,nCect $0 pl of the reference solution.

EUROPEAN PHARMACOPOEIA 5.0

Flu*entixol dihydrochloride

The test is not valid unless@ in the chromatogram obtained with the reference solution* the retention time of the peak due to fluoxetine is $0 min to $5 minD the retention time of the peak due to / trifluorometh&lphenol is not greater than .5 minD the h4v ratio is not greater than $.$ #h is the distance between the top of the peak due to impurit& 3 and the baselineD v is the distance between the top of the peak due to impurit& 3 and the lowest point of the valle& defined between the peak due to impurit& 3 and the peak due to fluoxetine%. ,f the ratio is greater than $.$* reduce the volume of methanol and increase the volume of the solution of trieth&lamine in the mobile phase. ,nCect $0 pl of test solution #a% and $0 pl of test solution #b%. 3ontinue the chromatograph& for . times the retention time of fluoxetine. ,n the chromatogram obtained with test solution #b%* the area of an& peak due to impurit& 3 is not greater than 0.00$5 times the area of the principal peak #0.$5 per cent%. ,n the chromatogram obtained with test solution #a%@ the areas of an& peaks due to impurit& " and impurit& ' are not greater than 0.0$25 times the area of the principal peak in the chromatogram obtained with test solution #b% #0.25 per cent%D none of the peaks* except the principal peak and the peaks due to impurit& " and impurit& '* has an area greater than 0.005 times the area of the principal peak in the chromatogram obtained with test solution #b% #0.$ per cent%D the sum of the areas of all the peaks* apart from the principal peak* is not greater than 0.025 times the area of the principal peak in the chromatogram obtained with test solution A. R + OH! ,1-./010,(ethyl2(ino/010*henyl*ro*2n010ol3 #b% #0.5 per cent%. solution is not greater than that of the Disregard an& peak with an area less than 4. R + H ! N0(ethyl010*henyl*ro*2n0102(ine3 0.0025 times that of the principal peak in corresponding peak in the chromatogram
1)1) See the information section on general monographs (cover pages)

the chromatogram obtained with test solution #b%. "cetonitrile. 9ot more than 0.$ per cent* determined b& gas chromatograph& #2.2.25%. Test solution. Dissolve 50 mg of the substance to be examined in dimeth&lformamide ! and dilute to 5.0 ml with the same solvent. !eference solution. To $.0 g of acetonitrile !* add dimeth&lformamide !* mix and dilute to $00.0 ml with the same solvent. Dilute $.0 ml of the solution to $000.0 ml with dimeth&lformamide !. The chromatographic procedure ma& be carried out using@ a fused silica capillar& column .0 m long and about 0.5. mm in internal diameter coated with macrogol 20 000 ! #$ pm thick%* helium for chromatograph& ! as the carrier gas at a flow rate of $0 ml4min* a flame ionisation detector* maintaining the temperature of the column at .5 :3 for min then raising the temperature at a rate of $5 :34min to 220 :3 and maintaining at 220 :3 for $0 min and maintaining the temperature of the inCection port and that of the detector at 250 :3. ,nCect $ pl of the test solution* $ pl of the reference solution and $ pl of the dissolution solvent. ,n the chromatogram obtained with the reference solution* note the retention time of acetonitrile. ,n the chromatogram obtained with the dissolution solvent* verif& that there is no peak with the same retention time as acetonitrile. The area of the peak due to acetonitrile in the chromatogram obtained with the test

Monographs

F-H

Fluoxetine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

obtained with the reference solution. -eav& metals #2./.5%. $.0 g complies with limit test 3 #20 ppm%. 7repare the standard using 2 ml of lead standard solution #$0 ppm 7b% !. Bater #2.5.$2%. 9ot more than 0.5 per cent* determined on g b& the semi micro determination of water. Sulphated ash #2./.$/%. 9ot more than 0.$ per cent* determined on $.0 g. "SS"( Examine b& li2uid chromatograph& #2.2.2<%. Test solution. Dissolve 55.0 mg of the substance to be examined in the mobile phase and dilute to 50.0 ml with the mobile phase. Dilute $0.0 ml of the solution to $00.0 ml with the mobile phase. !eference solution. Dissolve 55.0 mg of fluoxetine h&drochloride 3!S in the mobile phase and dilute to 50.0 ml with the mobile phase. Dilute $0.0 ml of the solution to ml with the mobile phase. The chromatographic procedure ma& be carried out using@ a stainless steel column 0.25 m long and /.? mm in internal diameter packed with oct&lsil&l silica gel for chromatograph& ! #5 pm%* as mobile phase at a flow rate of $ ml4min a mixture of 5 volumes of methanol !* .0 volumes of tetrah&drofuran ! and ?2 volumes of a solution of trieth&lamine ! prepared as follows@ to $0 ml of trieth&lamine !* add <50 ml of water !* mix and adCust to p- ?.0 with phosphoric acid ! #about /.5 ml% and dilute to $000 ml with water !* as detector a spectrophotometer set at 22) nm. Bhen using a recorder* adCust the sensitivit& of the s&stem so that the height of the principal peak in the chromatogram obtained with the reference solution is at

least 50 per cent of the full scale of the recorder. "dCust the volumes of methanol and the solution of trieth&lamine in the mobile phase so that the retention time of fluoxetine is between $0 min and $5 min. The assa& is not valid unless the s&mmetr& factor calculated at $0 per cent of the height of the peak due to fluoxetine is at most 2.0. ,nCect $0 pl of the test solution and $0 pl of the reference solution. 3alculate the content of fluoxetine h&drochloride #3$)-$<3l1.9;% from the area of the peaks in the chromatograms obtained with the test solution and the reference solution using the stated content of 3$)-$<3l1.9; in fluoxetine h&drochloride 3!S and correcting for the content of water and of acetonitrile in the substance to be examined. ,+76!,T,ES

9 3-. and enantiomer

EUROPEAN PHARMACOPOEIA 5.0

Flu*entixol dihydrochloride

Fluoxetine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

+obile phase@ water !* dieth&lamine !* meth&l eth&l ketone ! #$@/@<5 J4J4J%. "pplication@ 2 pl. Development@ twice over a path of $5 cm. Dr&ing@ in air. Detection " @ examine in ultraviolet light #.!S% 9 meth&l . phen&l . =. at 25/ nm. !esults " @ the principal spot #trifluorometh&l%phe nox&>propan $ in the chromatogram obtained with the amine. test solution is similar in position and siIe 0$42005@$?<. to the principal spot in the chromatogram 1867E9T,E;8 D,-(D!;3-8;!,DE obtained with the reference solution. 1lupentixoli dih&drochloridum Doubling of the spot ma& be observed in both chromatograms. Detection '@ spra& with alcoholic solution of sulphuric acid !D heat at $$0 :3 for 5 min and allow to coolD examine in ultraviolet light at .?5 nm. !esults '@ the principal spot in the 32.-2)3l21.92;S +r 50)./ chromatogram obtained with the test solution is similar in position and siIe to DE1,9,T,;9 the principal spot in the chromatogram 2 =/ =. =#FG% 2 #trifluorometh&l% <H obtained with the reference solution. thioxanthen < &lidene>prop&l>piperaIin Doubling of the spot ma& be observed in $ &l>ethanol dih&drochloride. 3ontent@ flupentixol dih&drochloride@ <5.0 per cent both chromatograms. +ix about 5 mg with /5 mg of heav& to $0$.5 per cent #dried substance%* magnesium oxide ! and ignite in a G isomer@ /2.0 per cent to 52.0 per cent. crucible until an almost white residue is 3-"!"3TE!S obtained #usuall& less than 5 min%. "llow "ppearance@ white or almost white to cool* add $ ml of water !* 0.05 ml of powder. Solubilit&@ ver& soluble in water* soluble phenolphthalein solution !$ and about $ ml of dilute h&drochloric acid ! to render in alcohol* practicall& insoluble in the solution colourless. 1ilter and add to meth&lene chloride. the filtrate a freshl& prepared mixture of ,DE9T,1,3"T,;9 1irst identification@ 0.$ ml of aliIarin S solution ! and 0.$ ml "* D. of Iircon&l nitrate solution !. +ix* allow Second identification@ '* 3* D. to stand for 5 min and compare the colour ,nfrared absorption spectrophotometr& of the solution with that of a blank #2.2.2/%. 3omparison@ flupentixol prepared in the same manner. The test dih&drochloride 3!S. solution is &ellow. The blank is red. Thin la&er chromatograph& #2.2.2)%. ,t gives reaction #a% of chlorides #2...$%. Test solution. Dissolve 20 mg of the TESTS substance to be examined in methanol ! and dilute to $0 ml with the same solvent. "ppearance of solution. The solution is clear #2.2.$% and not more intensel& !eference solution. Dissolve 20 mg of coloured than reference solution 0(? flupentixol dih&drochloride 3!S in #2.2.2* +ethod ,,%. methanol ! and dilute to $0 ml with the Dissolve 2.0 g of the substance to be same solvent. examined in water ! and dilute to 20 ml 7late@ T83 silica gel 125/ plate !.

Monographs

EUROPEAN PHARMACOPOEIA 5.0

Flu*entixol dihydrochloride

with the same solvent. p- #2.2..%@ 2.0 to ..0. Dissolve 0.5 g in carbon dioxide free water ! and dilute to 50 ml with the same solvent. !elated substances. Thin la&er chromatograph& #2.2.2)%. 3arr& out the test protected from light and prepare the solutions immediatel& before use. Test solution #a%. Dissolve 0./0 g of the substance to be examined in alcohol ! and dilute to 20 ml with the same solvent. Test solution #b%. Dilute 2.0 ml of test solution #a% to 20.0 ml with alcohol !. !eference solution #a%. Dilute $.0 ml of test solution #b% to ml with alcohol !. !eference solution #b%. Dilute 2.0 ml of reference solution #a% to 20.0 ml with alcohol !. !eference solution #c%. Dissolve $0 mg of flupentixol impurit& D 3!S in alcohol !* add 0.5 ml of test solution #a% and dilute to
General Notices (1) apply to all monographs and other texts

20.0 ml with alcohol !. 7late@ T83 silica gel 125/ plate !. +obile phase@ dieth&lamine !* toluene !* eth&l acetate ! #$0@20@)0 J4J4J%. "pplication@ 5 pl. Development@ in an unsaturated tank over a path of $0 cm. Dr&ing@ in air. Detection@ spra& with alcoholic solution of sulphuric acid!* heat at $$0 :3 for 5 min and allow to coolD examine in ultraviolet light at .?5 nm. Doubling of the spot due to flupentixol ma& be observed. S&stem suitabilit&@ the chromatogram obtained with reference solution #c% shows 2 clearl& separated spots. 8imits@ in the chromatogram obtained with test solution #a%@ an& spots* apart from the principal spot* are not more intense than the spot* or spots in the chromatogram obtained with reference solution #a% #0.2 per cent%*
1)15