Prepare to lesson 22

Theme: Pharmaceutical analysis of pyrazole (pyrazolone-3, pyrazolidine-3,5-dione) derivatives as drug substances: synthesis, properties, analysis, storage, action and use.

    

 

                                              

Derivatives of pirazolone-5 (pyrazyl ketone)

 

Phenazone

 

General Notices

   (Ph Eur monograph 0421)

Antipyrine

Antipyrinum

  Analgesin

  Sedatin                                                  

 

 

 C₁₁H₁₂N₂O   188.2  60-80-0

  

 Ph Eur

  

  

 DEFINITION

  

 Phenazone contains not less than 99.0 per cent and not more than the equivalent of  100.5 per cent of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, calculated with  reference to the dried substance.

  

Synthesis

         Synthesis of Phenazone (antipyrine) from phenylhydrazine and  acetacetic ester*

* Acetacetic ester synthesed by means of  Klyaizen reaction:  condensation two molecules of ethylacetate СН₃СООС₂Н₅ at heating in the presents sodium ethylate С₂Н₅ОNa:

 

 

 

Synthesis of  Phenazone consists of three stages.

 

1. Interaction Acetacetic ester with phenylhydrazine with formation phenylhydrazone acetacetic ester, and then 1-phenyl-3-methylpyrazolone-5:

 

2. Methylation the received product by means of methyliodide CH₃I or methyl ester of benzene sulphonic acid C₆H₅–SO₂–O–CH₃ with formation of intermediate product – salts of quarternary base:

 

 

3. Formation Phenazone at action of alkali NaOH on the received salt quarternary base:

 

CHARACTERS

  

 A white or almost white, crystalline powder or colourless crystals, very soluble in  water, in alcohol and in methylene chloride.

  

 IDENTIFICATION

  

 First identification A, B.

 

 Second identification A, C, D.

 

  A. Melting point (2.2.14): 109 °C to 113 °C.

 

  B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with phenazone CRS. Examine the substances prepared as discs using potassium bromide R.

 

  C. To 1 ml of solution S (see Tests) add 4 ml of water R and 0.25 ml of dilute sulphuric acid R. Add 1 ml of sodium nitrite solution R. A green colour develops.

  

 

 

Other reactions:

1. With solution of iron(ІІІ) chloride

0,1 g of drug dissolves in 10 ml of water R. To 2 ml of the received solution add 1 drop  30 g/l  solution iron(ІІІ) chloride R; there is intensive red colouring:

 

 

Red colouring attribute double salt of type: 3C₁₁H₁₂N₂O×2FeCl₃

2. Formation pyrazolone azo dye – specific reaction for Phenazone.

 Phenazone at first nitrosations by means of  sodium nitrite NaNO₂ at presence of CH₃COOH; exess nitric acid HNO₂ destroy by sodium azide NaN₃ (salt azide acid HN₃) then add a-naphthyl-amine; appears azo dye of  violet-red colouring.

 

 

 

                                       azo dye of  violet-red colouring

2. Reaction with an iodine solution.

At interaction with solution of iodine I₂ the white precipitate 4-iodopyrine is formed, which easily adsorbs iodine and quickly darkens.

 

 

3. Reaction with general-alkaloidal reagents (presence of tertiary Nitrogene)

At the expense of presence in a molecule of a tertiary Nitrogene Phenazone it is possible to consider as mild organic base, which can form salts.

Alkaloidal reagents precipitated  Phenazone from its water solution, forming precipitates of such colour:

– tannin – grey precipitate; picric acid – yellow; mercury bichloride HgCl₂ – white; solution KI₃ (reagent Bushard or Wagner) – brown; solution K₂ [HgI₄] (Mayer’s reagent) – yellow-orange, etc.

4. Specific reaction with 2-nitroindandione (very sensitive)

Preparation solution (1:20000) process the concentrated solution of 2-nitroindandione. There is an orange colouring which disappears at addition of ammonia NH₃.

 

 

TESTS

  

 Solution S

  

 Dissolve 2.5 g in carbon dioxide-free water R and dilute to 50 ml with the same  solvent.

  

 Appearance of solution

  

 Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

  

 Acidity or alkalinity

  

 To 10 ml of solution S add 0.1 ml of phenolphthalein solution R. The solution is  colourless. Add 0.2 ml of 0.01 M sodium hydroxide. The solution is red. Add 0.25 ml  of methyl red solution R and 0.4 ml of 0.01 M hydrochloric acid. The solution is red or  yellowish-red.

  

 Chlorides (2.4.4)

  

 10 ml of solution S diluted to 15 ml with water R complies with the limit test for  chlorides (100 ppm).

  

 Sulphates (2.4.13)

  

 Dissolve 1.5 g in distilled water R and dilute to 15 ml with the same solvent. The  solution complies with the limit test for sulphates (100 ppm).

  

 Heavy metals (2.4.8)

  

 12 ml of solution S complies with limit test A for heavy metals (20 ppm). Prepare the  standard using lead standard solution (1 ppm Pb) R.

  

 Loss on drying (2.2.32)

  

 Not more than 1.0 per cent, determined on 1.000 g by drying in vacuo at 60 °C for 6  h.

  

 Sulphated ash (2.4.14)

  

 Not more than 0.1 per cent, determined on 1.0 g.

  

 ASSAY

  

1.      Iodometry, back titration.

Dissolve 0.150 g in 20 ml of water R. Add 2 g of sodium acetate R and 25.0 ml of  0.05 M iodine. Allow to stand protected from light for 30 min. Add 25 ml of methylene  chloride R and shake until the precipitate dissolves. Titrate with 0.1 M sodium  thiosulphate, using 1 ml of starch solution R, added towards the end of the titration,  as indicator. Carry out a blank titration.

 

 1 ml of 0.05 M iodine is equivalent to 0,009411 g of C₁₁H₁₂N₂O.

 

 

 

The formed precipitate 4-iodoantipyrine (iodopyrine) can adsorb a quantity of iodine I₂ on the surface, therefore for precipitate dissolution add methylene  chloride (chloroform) (shake until the precipitate dissolves).

Sodium acetate CH₃COONa add for fixation formed iodide acid HI:

HI + CH₃COONa → NaI + CH₃COOH;

I₂ + 2Na₂S₂O₃ → 2NaI + Na₂S₄O₆.

Е_m = М m./2

 

 

  

 STORAGE

  

 Store protected from light (list of strong means!).

  

 

  Ph Eur

 

 

 

Action and use

Anaesthetic, antipyretic, resolvent.

Release forms: a powder and tablets – 0,25 g.

 

 

 

 

 

 

 

 

 

Dipyrone

General Notices

  

   (Metamizole Sodium, Ph Eur monograph 1346)

 

 

 

 

 

 

 C₁₃H₁₆N₃NaO₄S,H₂O  351.4   5907-38-0

  Analginum

  Analgetin

 

 DEFINITION

  

 Metamizole sodium contains not less than 99.0 and not more than the equivalent of  100.5 per cent of sodium [(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N-methylamino]methanesulphonate, calculated with  reference to the dried substance.

  

Synthesis

         Synthesis from 4-aminoantipyrine

         Synthesis consists 3 stages.

1. Interaction 4-aminoantipyrine with benzaldehyde С₆Н₅СНО with formation benzylidenaminoantipyrine:

 

2. Methylation benzylidenaminoantipyrine by means of dimethylsulphate (СН₃) ₂SO₄ with formation 4-methylaminoantipyrine:

 

3. Interaction 4-methylaminoantipyrine with a mix of solutions of formaldehyde НСНО and sodium hydrogensulphyde NaHSO₃ (differently НО–СН₂–SO₃Na):

 

 

CHARACTERS

  

 A white or almost white, crystalline powder, very soluble in water, soluble in alcohol.

  

 IDENTIFICATION

  

 First identification A, D.

 

 Second identification B, C, D.

 

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

 

  B. Oxidation of preparation by means of  strong hydrogen peroxide solution.

Dissolve 50 mg in 1 ml of strong hydrogen peroxide solution R. A blue colour is produced which fades rapidly and turns to intense red in a few minutes.

 

  C. Oxidation of preparation by means of potassium iodate with the next  revealing of products of oxidation

Place 0.10 g in a test tube, add some beads of glass and dissolve the substance in 1.5 ml of water R. Add 1.5 ml of dilute hydrochloric acid R and place a filter paper wetted with a solution of 20 mg of potassium iodate R in 2 ml of starch solution R at the open end of the test tube. Heat gently, the evolving vapour of sulphur dioxide colours the filter paper blue. After heating gently for 1 min take a glass rod with a drop of a 10 g/l solution of chromotropic acid, sodium salt R in sulphuric acid R and place in the opening of the tube. Within 10 min, a blue-violet colour develops in the drop of the reagent.

 

 

 

                 

aurin dye of blue-violet colour

 

а) 5SO₂ + 2KIO₃ ® I₂ + 4SO₃ + K₂SO₄

 

 

D. 0.5 ml of solution S (see Tests) gives reaction (a) of sodium (2.3.1).

Na⁺ + [Sb(OH)₆]^–  Na[Sb(OH)₆]

                                     white

  

Other reaction:

1. Heating of preparation with mineral acids

         0,2 g preparation heat up about 2 ml with diluted HCl; the sharp smell of sulphurous gas SO₂, and then formaldehyde НСНО is at first audible.

         Chemism of acid hydrolysis (at the expense of decomposition methylensulphite-SN₂SO₃Na) it is possible to present such equation:

It is distinctive reaction of analginum from antipyrine.

 

TESTS

  

 Solution S

  

 Dissolve 2.0 g in carbon dioxide-free water R and dilute to 40 ml with the same  solvent.

  

 Appearance of solution

  

 Solution S is clear (2.2.1) and immediately after preparation, not more intensely  coloured than reference solution BY₆ (2.2.2, Method I).

  

 Acidity or alkalinity

  

 To 5 ml of solution S, add 0.1 ml of phenolphthalein solution R1. The solution is  colourless. Not more than 0.1 ml of 0.02 M sodium hydroxide is required to change  the colour of the indicator to pink.

  

 Related substances

  

 Examine by liquid chromatography (2.2.29).

 

 Prepare the solutions immediately before use.

 

 Test solution Dissolve 50.0 mg of the substance to be examined in methanol R and  dilute to 10.0 ml with the same solvent.

 

 Reference solution (a) Dissolve 10.0 mg of metamizole impurity A CRS in methanol  R and dilute to 20.0 ml with the same solvent.

 

 Reference solution (b) Dilute 1.0 ml of reference solution (a) to 20.0 ml with  methanol R.

 

 Reference solution (c) Dissolve 40 mg of metamizole sodium CRS in methanol R  and dilute to 20.0 ml with the same solvent.

 

 Reference solution (d) Take 10 ml of reference solution (c) and boil under a reflux  condenser for 10 min. Allow to cool to room temperature and dilute to 20.0 ml with  methanol R.

 

 Reference solution (e) To 6 ml of reference solution (a) add 1 ml of reference  solution (c).

 

 The chromatographic procedure may be carried out using:

  

  —a stainless steel column 0.25 m long and 4.6 mm in internal diameter packed with base-deactivated octadecylsilyl silica gel for chromatography R (5 µm),

  

  —as mobile phase at a flow rate of 1.0 ml/min a mixture of 28 volumes of methanol R and 72 volumes of a buffer solution prepared by adjusting a mixture of 1000 volumes of a 6.0 g/l solution of sodium dihydrogen phosphate R and 1 volume of triethylamine R to pH 7.0 with strong sodium hydroxide solution R,

  

  —as detector a spectrophotometer set at 254 nm.

 

 When the chromatograms are recorded in the prescribed conditions, the substances  elute in the following order: impurity A, metamizole, impurity B, impurity C and  impurity D. Inject 10 µl of reference solution (b). Adjust the sensitivity of the system  so that the height of the principal peak in the chromatogram obtained is at least 50  per cent of the full scale of the recorder.

 

 Inject 10 µl of reference solution (d). The chromatogram shows two principal peaks  due to metamizole and impurity C.

 

 Inject 10 µl of reference solution (e). The test is not valid unless in the chromatogram  obtained the resolution between the peaks corresponding to impurity A and  metamizole is at least 2.5.

 

 Inject 10 µl of the test solution and 10 µl of reference solution (b) and continue the  chromatography for 3.5 times the retention time of metamizole. In the chromatogram  obtained with the test solution: the area of any peak corresponding to impurity C is  not greater than the area of the principal peak in the chromatogram obtained with  reference solution (b) (0.5 per cent), the area of any peaks, apart from the principal  peak and the peak due to impurity C is not greater than 0.4 times the area of the  principal peak in the chromatogram obtained with reference solution (b) (0.2 per  cent). The sum of the areas of all the peaks, apart from the principal peak, is not  greater than the area of the principal peak in the chromatogram obtained with  reference solution (b) (0.5 per cent). Disregard any peak with an area less than 0.05  times that of the principal peak in the chromatogram obtained with the reference  solution (b).

  

  

 Sulphates (2.4.13)

  

 Dissolve 0.150 g in distilled water R and dilute to 15 ml with the same solvent. The  solution complies with the limit test for sulphates (0.1 per cent).

  

 Heavy metals (2.4.8)

  

 Dissolve 2.0 g in water R and dilute to 20 ml with the same solvent. 12 ml of the  freshly prepared solution complies with limit test A for heavy metals (20 ppm).  Prepare the standard using lead standard solution (2 ppm Pb) R.

  

 Loss on drying (2.2.32)

  

 4.9 per cent to 5.3 per cent, determined on 1.000 g by drying in an oven at 100 °C to  105 °C.

 

 

 

 

 

IMPURITIES

  

 

 

 

 

 

 

 

 

 

  

  A. R = NHCHO: 4-formylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one,

 

  B. R = NH₂: 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one,

 

  C. R = NHCH₃: 4-methylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one,

 

  D. R = N(CH₃)₂: 4-dimethylamino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one.

  

 

  Ph Eur

 

  

 

 ASSAY

  

Iodometry, direct titration

 Dissolve 0.200 g in 10 ml of 0.01 M hydrochloric acid previously cooled in iced water  and titrate immediately, dropwise, with 0.05 M iodine. Before each addition of 0.05 M  iodine dissolve the precipitate by swirling. At the end of the titration add 2 ml of  starch solution R and titrate until the blue colour of the solution persists for at least 2  min. The temperature of the solution during the titration must not exceed 10 °C.

 

 1 ml of 0.05 M iodine is equivalent to 16.67 mg of C₁₃H₁₆N₃NaO₄S.

  

 

 

Еm (C₁₃H₁₆N₃NaO₄S, H₂O) = М m./2

 

 

STORAGE

  

 Store protected from light.

 

 

Action and use

  

 Analgesic.

  

 Ph Eur

  

 

  

 

 

 

 

                                      Propiphenazonum (latin name)     

(not pharmacopoeial drug)

 Budirol

  Causytin

The chemical name: 1-phenyl-2,3-dimethyl-4-isopropyl-pyrazolone-5

(4-isopropylantipyrine).

 

CHARACTERS

  

 Appearance

  

 White or slightly yellowish crystal powder without a smell, bitter taste.

 

Solubility

  

 Slightly soluble in water, freely soluble in alcohol, methylenchloride, chloroform and ether.  

 

         Chemical properties

Unlike antipyrine  propiophenazonum shows the expressed reducing properties, because it is derivative partially hydrogenated pyrazoline and is presence alkyl radical at С₄, interfering reactions, characteristic for antipyrine.

Like analginum propiophenazonum is oxidised even slight oxidizers.

Identification

1. IR-spectroscopy

The IR-spectrum of substance received in disks with KBr, should correspond to spectrum propiophenazone.

2. UV-spectroscopy

On a spectrum of water solution of substance maxima are observed at length of wave of 240 nanometers.

3. Reaction with solution silver nitrate

At action on solution of substance of solution silver nitrate AgNO₃ there is a violet colouring, and then precipitate of grayish-brown colour (precipitate of metal silver).

 

 

 

 

4. Reaction with solution of iron (ІІІ) chloride

At action on water-alcoholic solution of substance several drops of solution iron(ІІІ) chloride FeCl₃ there is a red-brown colouring passing after addition chloride acid HCl in the yellow.

         5. Reaction with generalalkaliodal reagents (on tertiary atom of Nitrogene)

With generalalkaliodal reagents the preparation forms precipitates of complex salts.

Assay

         1. Acidimetry, non-aqueous titration

         Shot of substance dissolve  in dioxane and titrate with standard solution перхлоратной acids HClO₄ in the presence of ice  СН₃СООН (indicator – crystal violet).

 

2. Differential UV-spectrophotometry.

3. A highly effective liquid chromatography (in medicinal forms).

        

Storage

The list of strong substances. In densely corked container, in the place protected from light.

 

Action and use

 Anaesthetic, antipyretic, resolvent.

         Is a part of the combined preparations.

 

 

 

 

 

 

 

Derivatives of pyrazolidine-3,5-dione

 

Phenylbutazone

General Notices

  

 

 (Ph Eur monograph 0422)

 

Phenylbutazonum*                                                                                                                 Butadion

Butadionum

 Pyrazolidin

 

 

 

 

 

 C₁₉H₂₀N₂O₂  308.4  50-33-9

  

 DEFINITION

  

 4-Butyl-1,2-diphenylpyrazolidine-3,5-dione.

  

 Content

  

 99.0 per cent to 101.0 per cent (dried substance).

 

Synthesis

 

Condensation diethyl ester of butylmalonic acid with hydrazono-benzene.

         Diethyl ester of butylmalonic acid synthesed by condensation diethyl ester of malonic acid with butylbromide C₄H₉Br in the presence of condensing agents (sodium ethylate C₂Н₅ОNa).

Hydrazono-benzene  synthesed by reduction of nitrobenzene С₆Н₅NO₂ by a Zn-heat in ethanol solution KOH.

         The synthesis scheme of phenylbutazone:

        

  

 CHARACTERS

  

 Appearance

  

 White or almost white, crystalline powder.

  

 Solubility

  

 Practically insoluble in water, sparingly soluble in alcohol. It dissolves in alkaline  solutions.

  

 IDENTIFICATION

  

 First identification A, C.

 

 Second identification A, B, D.

 

  A. Melting point (2.2.14): 104 °C to 107 °C.

 

  B. Thin-layer chromatography (2.2.27).  

 

 Test solution Dissolve 25 mg of the substance to be examined in a mixture of equal  volumes of ethanol R and methylene chloride R and dilute to 25 ml with the same  mixture of solvents.

 

 Reference solution Dissolve 25 mg of phenylbutazone CRS in a mixture of equal  volumes of ethanol R and methylene chloride R and dilute to 25 ml with the same  mixture of solvents.

 

 Plate TLC silica gel GF₂₅₄plate  R.

 

 Mobile phase acetone R, methylene chloride R (20:80 V/V).

 

 Application 5 µl.

 

 Development Over a path of 10 cm.

 

 Drying In air.

 

 Detection Examine in ultraviolet light at 254 nm.

 

 Results 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  the reference solution.

 

  C. Infrared absorption spectrophotometry (2.2.24).

 

 Comparison phenylbutazone CRS.

 

  D. Reaction of oxidation by sodium nitrite in the acetic medium

To 0.1 g add 1 ml of glacial acetic acid R and 2 ml of hydrochloric acid R and heat the mixture under a reflux condenser for 30 min. Cool, add 10 ml of water R and filter. To the filtrate add 3 ml of a 7 g/l solution of sodium nitrite R. A yellow colour is produced. To 1 ml of the solution add a solution of 10 mg of -naphthol R in 5 ml of sodium carbonate solution R. A brownish-red to violet-red precipitate is formed.

Chemism. Reaction is based on splitting (decomposition) of butadiene molecule and oxidation of  hydrazono-benzene С₆Н₅–NH–NH–C₆H₅ to painted azobenzene: С₆Н₅–N=N–C₆H₅:

        

Other reactions:

1. Reaction with solutions of heavy metals salts

With solutions of heavy metals salts (CuSO₄, AgNO₃, FeCl₃) butadion-sodium forms insoluble in water painted salts:

   a) reaction of alkaline solution of preparation with solution of copper sulphate

         Some crystals (0,05 g) substance shake up about 1,5 ml 0,1М solution of sodium hydroxide NaOH during 2 mines, filtered and to filtrate add 0,5 ml of solution CuSO₄; the precipitate of grayish colour passing in light- blue is formed.

 

            

b) reaction with  solution of silver nitrate

At interaction of alkaline solution of preparation with solution of silver nitrate AgNO₃ the white precipitate of Silver salt is formed.

  c) reaction with solution of iron(ІІІ) chloride

At interaction of alkaline solution of preparation with solution of iron(ІІІ) chloride FeCl₃ the brown precipitate of Iron(ІІІ) salt is formed.

  

 

 TESTS

  

 Solution S

  

 Dissolve 1.0 g with shaking in 20 ml of dilute sodium hydroxide solution R and  maintain the solution at 25 °C for 3 h.

  

 Appearance of solution

  

 Solution S is clear (2.2.1).

  

 Acidity or alkalinity

  

 Heat to boiling 1.0 g in 50 ml of water R, cool with shaking in a closed flask and filter.  To 25 ml of the filtrate add 0.5 ml of phenolphthalein solution R. The solution is  colourless. Not more than 0.5 ml of 0.01 M sodium hydroxide is required to change  the colour of the indicator. Add 0.6 ml of 0.01 M hydrochloric acid and 0.1 ml of  methyl red solution R; the solution is red or orange.

  

 Absorbance (2.2.25)

  

 Maximum 0.20 for solution S at 420 nm in a 4 cm cell.

  

 Related substances

  

 Liquid chromatography (2.2.29). Prepare the solutions immediately before use.

 

 Test solution Dissolve 100.0 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. Dilute 1.0 ml to 10.0 ml with acetonitrile R.

 

 Reference solution (b) Dissolve 5 mg of phenylbutazone impurity B CRS and 5 mg  of 1,2-diphenylhydrazine R in acetonitrile R, add 0.5 ml of the test solution and dilute  to 50 ml with acetonitrile R. Dilute 2.5 ml to 10 ml with acetonitrile R.

 

 Reference solution (c) Dissolve 1.0 mg of benzidine R in acetonitrile R and dilute to  100.0 ml with the same solvent. Dilute 1.0 ml to 100.0 ml with acetonitrile R. Dilute  5.0 ml to 10.0 ml with acetonitrile R.

 

 Column: 

  —size: l = 0.125 m, Ш = 4.0 mm,

  

  —stationary phase: octadecylsilyl silica gel for chromatography R (5 µm),  

  

  —temperature: 30 °C.

 

 Mobile phase:

  —mobile phase A: dissolve 1.36 g of sodium acetate R in water R, adjust to pH 5.2 with a 52.5 g/l solution of citric acid R and dilute to 1000 ml with water R,  

  

  —mobile phase B: acetonitrile R,

  

 

 

 

 

 

  

 Flow rate 1.5 ml/min.

 

 Detection Spectrophotometer at 240 nm.

 

 Injection 20 µl; inject the test solution and reference solutions (a) and (b).

 

 Relative retentions with reference to phenylbutazone (retention time = about 13 min):  impurity E = about 0.2; impurity A = about 0.5; impurity B = about 1.2; impurity C =  about 1.3; impurity D = about 1.7.

 

 System suitability Reference solution (b):

  

  —resolution: minimum 2.0 between the peaks due to phenylbutazone and to impurity B.

 

 Limits:

  —correction factor: for the calculation of content, multiply the peak area of impurity C by 0.55,

  

  —impurities A, B: for each impurity, not more than 2.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.25 per cent),

  

  —impurity C: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.20 per cent),

  

  —any other impurity: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent),

  

  —total: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent),

  

  —disregard limit: 0.25 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.025 per cent); disregard any peak due to impurity E.

  

  

 Impurity E

  

 Liquid chromatography (2.2.29) as described in the test for related substances with  the following modifications.

 

 Detection Spectrophotometer at 280 nm.

 

 Injection Test solution and reference solution (c).

 

 System suitability Reference solution (c):

  

  —signal-to-noise ratio: minimum 10 for the principal peak.

 

 Limit:

  —impurity E: not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (5 ppm).

  

  

 Heavy metals (2.4.8)

  

 Maximum 20 ppm.

 

 1.0 g complies with limit test C. Prepare the standard using 2 ml of lead standard  solution (10 ppm Pb) R.

  

 Loss on drying (2.2.32)

  

 Maximum 0.2 per cent, determined on 1.000 g by drying in vacuo at 80 °C for 4 h.

  

 Sulphated ash (2.4.14)

  

 Maximum 0.1 per cent, determined on 1.0 g.

 

IMPURITIES

  

 

 

 

 

 

 

 

 

 

 

  

  A. (2RS)-2-[(1,2-diphenyldiazanyl)carbonyl]hexanoic acid,

  

 

 

 

 

 

 

 

 

 

 

  

  B. 4-butyl-4-hydroxy-1,2-diphenylpyrazolidine-3,5-dione,

 

  C. C₆H₅-NH-NH-C₆H₅: 1,2-diphenyldiazane, (1,2-diphenylhydrazine),

 

  D. C₆H₅-N=N-C₆H₅: 1,2-diphenyldiazene,

  

 

 

 

 

 

 

 

  

  E. biphenyl-4,4-diamine (benzidine).

  

 

  Ph Eur

 

  

 ASSAY

 Alkalimetry, direct titration in the presence of acetone (acid properties of phenylbutazone)

 

 Dissolve 0.250 g in 25 ml of acetone R and add 0.5 ml of bromothymol blue solution  R1. Titrate with 0.1 M sodium hydroxide until a blue colour is obtained which persists  for 15 s. Carry out a blank titration.  

 

 1 ml of 0.1 M sodium hydroxide is equivalent to 30.84 mg of C₁₉H₂₀N₂O₂.

 

 

 

 

E_m (C₁₉H₂₀N₂O₂) = М m.

 

 

  

 STORAGE

  

 Protected from light.

 

Action and use

  

 Anti-inflammatory; analgesic.

  

 Ph Eur

  

  

 

Tribuzonum*

 

 

 

 

 

 

The chemical name: 4 (4,4-dimethyl-3-oxopenthyl)-1,2-diphenyl-pyrazolidindione-3,5

 

Tribuzonum show anti-inflammatory, analgetic and febrifugal (antipyretic) action. Reduces aggregation thrombocytes and strengthens fibrinolysis.

Apply at inflammatory processes blood vessels (thrombophlebitises, a phlebitis, sharp and chronic thromboses), at pseudorheumatism, spondylosis, artroses, etc.

The release form: tablets for 0,25

Storage. The list of strong substances. In Czechia let out tablets “Benetazine”.