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Contrôle « qualité » des médicaments

Un médicament (produit fini) a une forme pharmaceutique (comprimé, sirop,


suppositoire, inhalation, forme injectable…)
Il est composé de matières premières (principe(s) actifs et excipient(s))

Le contrôle physico-chimique des médicaments est réglementé, cela veut dire qu’un
médicament ne peut pas être commercialisé s’il ne passe pas par le règlement
établi dans les Pharmacopées.

Une pharmacopée peut être nationale (pharmacopée Américaine USP, British


Pharmacopoeia BP, pharmacopée japonaise, pharmacopée indienne ….) ou régionale
(pharmacopée Européenne EP)

Une pharmacopée comporte en grande partie les méthodes de contrôle appelées


monographes des principes actifs, excipients et produits finis.

Pour un même principe actif, les monographies peuvent différer d’une


pharmacopée à une autre.

Les pharmacopées les plus importantes sont l’USP, l’EP, la BP et la JP.


Les plus utilisées sont l’USP, l’EP, la BP

Les Monographes du principe actif se trouvent dans toutes les monographies


Les Monographes du produit fini se trouvent dans l’USP et BP et pas dans l’EP
Exemples
Remarque importante : Ces exemples sont donnés juste pour
préciser les points importants et nécessaires pour la libération
d’un principe actif ou d’un produit fini

IBUPROFENE
Matière première
BP EP
(Ph. Eur. monograph 0721)

C13H18O2 Mr 206,3[15687-27-1]
DÉFINITION

C13H18O2 206.3 15687-27-1

Action and use

Cyclo-oxygenase inhibitor; analgesic; anti-


inflammatory.

Preparations

Ibuprofen Cream

Ibuprofen Gel

Ibuprofen Oral Suspension

Ibuprofen Tablets

Prolonged-release Ibuprofen Capsules


Acide (2RS)-2-[4-(2-
Prolonged-release Ibuprofen Tablets
méthylpropyl)phényl]propanoïque.
Teneur : 98,5 pour cent à 101,0 pour cent
Ph Eur (substance desséchée).

DEFINITION CARACTÈRES
Aspect : poudre cristalline, blanche ou
(2RS)-2-[4-(2- sensiblement blanche ou
Methylpropyl)phenyl]propanoic acid. cristaux incolores.
Solubilité : pratiquement insoluble dans l’eau,
Content facilement
soluble dans l’acétone, dans le méthanol et dans le
chlorure de
98.5 per cent to 101.0 per cent (dried méthylène. L’ibuprofène se dissout dans les
substance). solutions diluées
d’hydroxydes et de carbonates alcalins.
CHARACTERS

Appearance
IDENTIFICATION
Première identification : A, C.
White or almost white, crystalline powder
Seconde identification : A, B, D.
or colourless crystals.
A. Point de fusion (2.2.14) : 75 °C à 78 °C.
Solubility B. Spectrophotométrie
Practically insoluble in water, freely soluble d’absorption dans
in acetone, in methanol and in methylene chloride.
It dissolves in dilute solutions of alkali hydroxides
l’ultraviolet et le
visible (2.2.25).
and carbonates.
Solution à examiner. Dissolvez 50,0 mg
d’ibuprofène dans
IDENTIFICATION une solution d’hydroxyde de sodium R à 4 g/L et
complétez
First identification A, C  à 100,0 mL avec la même solution alcaline.
Région spectrale : 240-300 nm, à l’aide d’un
spectrophotomètre dont la largeur de bande est de
Second identification A, B, D  1,0 nm et
la vitesse maximale de balayage de 50 nm/min.
 A. Melting point (2.2.14): 75 °C to 78 Maximums d’absorption : à 264 nm et 272 nm.
°C. Epaulement : à 258 nm.
Rapport des absorbances :
 B. Ultraviolet and visible absorption — A264 / A258 = 1,20 à 1,30,
spectrophotometry (2.2.25). — A272 / A258 = 1,00 à 1,10.
C. Spectrophotométrie d’absorption dans
l’infrarouge (2.2.24).
Test solution  Dissolve 50.0 mg in a 4 Comparaison : ibuprofène SCR.
g/L solution of sodium hydroxide R and dilute to D. Chromatographie sur couche mince (2.2.27).
100.0 mL with the same alkaline solution. Solution à examiner. Dissolvez 50 mg d’ibuprofène
dans
du chlorure de méthylène R et complétez à 10 mL
Spectral range  240-300 nm, using a avec le
spectrophotometer with a band width of 1.0 nm même solvant.
and a scan speed of not more than 50 nm/min. Solution témoin. Dissolvez 50mg d’ibuprofène SCR
dans
Absorption maxima  At 264 nm and 272 du chlorure de méthylène R et complétez à 10 mL
nm. avec le
même solvant.
Plaque : plaque au gel de silice pour CCM R.
Shoulder  At 258 nm. Phase mobile : acide acétique anhydre R, acétate
d’éthyle R,
Absorbance ratio:   — A264 / A258 = 1.20 hexane R (5:24:71 V/V/V).
to 1.30; Dépôt : 5 μL.
  — A272 / A258 = 1.00 to 1.10. Développement : sur un parcours de 10 cm.
Séchage : à 120 °C pendant 30 min.
 C. Infrared absorption Détection : pulvérisez légèrement une solution de
spectrophotometry (2.2.24). permanganate de potassium R à 10 g/L dans
l’acide
sulfurique dilué R et chauffez à 120 °C pendant 20
Comparison  ibuprofen CRS. min.
Examinez en lumière ultraviolette à 365 nm.
 D. Thin-layer chromatography (2.2.27). Résultats : la tache principale du chromatogramme
obtenu
avec la solution à examiner est semblable quant à
Test solution  Dissolve 50 mg of the sa position,
substance to be examined in methylene chloride R sa coloration et ses dimensions à la tache
and dilute to 10 mL with the same solvent. principale duchromatogramme obtenu avec la solu
tion témoin.
Reference solution  Dissolve 50 mg of
ibuprofen CRS in methylene chloride R and dilute ESSAI
to 10 mL with the same solvent. Solution S. Dissolvez 2,0 g d’ibuprofène dans du méthanol
R et
complétez à 20 mL avec le même solvant.
Plate  TLC silica gel plate R. Aspect de la solution. La solution S est limpide (2.2.1) et
incolore (2.2.2, Procédé II).
Mobile phase  anhydrous acetic acid R, Angle de rotation optique (2.2.7) : − 0,05° à + 0,05°.
ethyl acetate R, hexane R (5:24:71 V/V/V). Dissolvez 0,50 g d’ibuprofène dans du méthanol R et
complétez
à 20,0 mL avec le même solvant.
Application  5 µL. Substances apparentées.
Chromatographie liquide (2.2.29).
Development  Over a path of 10 cm. Solution à examiner. Dissolvez 20 mg d’ibuprofène dans 2
mL
d’acétonitrile R1 et complétez à 10,0 mL avec la phase
Drying  At 120 °C for 30 min. mobile A.
Solution témoin (a). Prélevez 1,0 mL de solution à examiner
et
Detection  Lightly spray with a 10 g/L complétez à 100,0 mL avec la phase mobile A. Prélevez 1,0
solution of potassium permanganate R in dilute mL
sulfuric acid R and heat at 120 °C for 20 min; de cette solution et complétez à 10,0 mL avec la phase
examine in ultraviolet light at 365 nm. mobile A.
Solution témoin (b). Prélevez 1,0mL d’impureté B
d’ibuprofène SCR et complétez à 10,0 mL avec de
Results  The principal spot in the l’acétonitrile R1 (solution A). Dissolvez 20 mg
chromatogram obtained with the test solution is d’ibuprofène SCR
similar in position, colour and size to the principal dans 2 mL d’acétonitrile R1, ajoutez 1,0 mL de solution A
spot in the chromatogram obtained with the et
reference solution. complétez à 10,0 mL avec la phase mobile A.
Solution témoin (c). Dissolvez le contenu d’un flacon
TESTS d’ibuprofène pour identification des pics SCR (mélange des
impuretés A, J et N) dans 1 mL d’acétonitrile R1 et
complétez à
Solution S 5 mL avec la phase mobile A.
Colonne :
Dissolve 2.0 g in methanol R and dilute to — dimensions : l = 0,15 m, Ø = 4,6 mm,
20 mL with the same solvent. — phase stationnaire : gel de silice octadécylsilylé pour
chromatographie R (5 μm).
Appearance of solution Phase mobile :
— phase mobile A : mélangez 0,5 volume d’acide
phosphorique R, 340 volumes d’acétonitrile R1 et
Solution S is clear (2.2.1) and colourless 600 volumes d’eau R. Laissez équilibrer et complétez à
(2.2.2, Method II). 1000 volumes avec de l’eau R,
— phase mobile B : acétonitrile R1,
Optical rotation (2.2.7) Intervalle
(min)
Phase mobile A
-0.05° to + 0.05°. (pour cent V/V)
Phase mobile B
(pour cent V/V)
Dissolve 0.50 g in methanol R and dilute to 0 - 25 100 0
20.0 mL with the same solvent. 25 - 55 100 → 15 0 → 85
55 - 70 15 85
Débit : 2mL/min.
Related substances Détection : spectrophotomètre à 214 nm.
Injection : 20 μL.
Liquid chromatography (2.2.29). Identification des impuretés : utilisez le chromatogramme
fourni avec l’ibuprofène pour identification des pics SCR et
Test solution  Dissolve 20 mg of the le chromatogramme obtenu avec la solution témoin (c) pour
substance to be examined in 2 mL of acetonitrile identifier les pics dus aux impuretés A, J et N.
R1 and dilute to 10.0 mL with mobile phase A. Rétention relative par rapport à l’ibuprofène (temps de
rétention = environ 21 min) : impureté J = environ 0,2 ;
impureté N = environ 0,3 ; impureté A = environ 0,9 ;
Reference solution (a)  Dilute 1.0 mL of impureté B = environ 1,1.
the test solution to 100.0 mL with mobile phase A. Conformité du système : solution témoin (b) :
Dilute 1.0 mL of this solution to 10.0 mL with mobile — rapport pic/vallée : au minimum 1,5 avec Hp = hauteur
phase A. au-dessus de la ligne de base du pic dû à l’impureté B et
Hv = hauteur au-dessus de la ligne de base du point le plus
bas
Reference solution (b)  Dilute 1.0 mL of du tracé entre ce pic et celui dû à l’ibuprofène. Si
ibuprofen impurity B CRS to 10.0 mL with nécessaire,
acetonitrile R1 (solution A). Dissolve 20 mg of ajustez la concentration en acétonitrile de la phase mobile
ibuprofen CRS in 2 mL of acetonitrile R1, add 1.0 A.
mL of solution A and dilute to 10.0 mL with mobile Limites :
phase A. — impuretés A, J, N : pour chaque impureté, au maximum
1,5
fois la surface du pic principal du chromatogramme obtenu
Reference solution (c)  Dissolve the avec la solution témoin (a) (0,15 pour cent),
contents of a vial of ibuprofen for peak — impuretés non spécifiées : pour chaque impureté,
identification CRS (mixture of impurities A, J and N) au maximum 0,5 fois la surface du pic principal du
in 1 mL of acetonitrile R1 and dilute to 5 mL with chromatogramme obtenu avec la solution témoin (a)
mobile phase A. (0,05 pour cent),
— total : au maximum 2 fois la surface du pic principal
du chromatogramme obtenu avec la solution témoin (a)
Column:
(0,2 pour cent),
 — size: l = 0.15 m, Ø = 4.6 mm;
— limite d’exclusion : 0,3 fois la surface du pic principal
 — stationary phase: octadecylsilyl silica du chromatogramme obtenu avec la solution témoin (a)
gel for chromatography R (5 µm). (0,03 pour cent).
Impureté F. Chromatographie en phase gazeuse (2.2.28) :
Mobile phase: utilisez le procédé de normalisation.
Solution de méthylation. Prélevez 1 mL de
 — mobile phase A: mix 0.5 volumes of
N,Ndiméthylformamide
phosphoric acid R, 340 volumes of acetonitrile R1
diméthylacétal R et 1 mL de pyridine R et
and 600 volumes of water R; allow to equilibrate complétez à 10 mL avec de l’acétate d’éthyle R.
and dilute to 1000 volumes with water R; Solution à examiner. Pesez environ 50,0 mg d’ibuprofène
 — mobile phase B: acetonitrile R1; dans
un flacon scellable, dissolvez dans 1,0 mL d’acétate
d’éthyle R,
ajoutez 1 mL de solution de méthylation, scellez et chauffez
à
100 °C dans un bloc chauffant pendant 20 min. Laissez
refroidir.
Evaporez les réactifs sous un courant d’azote à température
ambiante. Dissolvez le résidu dans 5 mL d’acétate d’éthyle
R.
Solution témoin (a). Dissolvez 0,5 mg d’impureté F
d’ibuprofène SCR dans de l’acétate d’éthyle R et complétez
à
Flow rate  2 mL/min. 10,0 mL avec le même solvant.
Solution témoin (b). Pesez environ 50,0 mg d’ibuprofène
SCR
Detection  Spectrophotometer at 214 dans un flacon scellable, dissolvez dans 1,0 mL de solution
nm. témoin (a), ajoutez 1 mL de solution de méthylation, scellez
et chauffez à 100 °C dans un bloc chauffant pendant 20
min.
Injection  20 µL.
Laissez refroidir. Evaporez les réactifs sous un courant
d’azote à
Identification of impurities  Use the température ambiante. Dissolvez le résidu dans 5 mL
chromatogram supplied with ibuprofen for peak d’acétate
identification CRS and the chromatogram obtained d’éthyle R.
Colonne :
with reference solution (c) to identify the peaks due
to impurities A, J and N. — matériau : silice fondue,
— dimensions : l = 25 m, Ø = 0,53 mm,
— phase stationnaire : macrogol 20 000 R (épaisseur du
Relative retention  With reference to film
ibuprofen (retention time = about 21 min): impurity 2 μm).
J = about 0.2; impurity N = about 0.3; impurity A = Gaz vecteur : hélium pour chromatographie R.
about 0.9; impurity B = about 1.1. Débit : 5,0mL/min.
Température :
System suitability: reference solution (b): — colonne : 150 °C,
 — peak-to-valley ratio: minimum 1.5, — chambre à injection : 200 °C,
where Hp = height above the baseline of the peak — détecteur : 250 °C.
Détection : ionisation de flamme.
due to impurity B, and Hv = height above the
Injection : 1 μL de solution à examiner et de solution
baseline of the lowest point of the curve separating
témoin (b).
this peak from the peak due to ibuprofen. If
Enregistrement : 2 fois le temps de rétention de
necessary, adjust the concentration of acetonitrile l’ibuprofène.
in mobile phase A. Conformité du système :
— rétention relative par rapport à l’ibuprofène (temps de
Limits: rétention = environ 17 min) : impureté F = environ 1,5.
 — impurities A, J, N: for each impurity, Limite :
not more than 1.5 times the area of the principal — impureté F : au maximum 0,1 pour cent.
peak in the chromatogram obtained with reference Métaux lourds (2.4.8) : au maximum 10 ppm.
solution (a) (0.15 per cent); 12 mL de solution S satisfont à l’essai B. Préparez la
solution
 — unspecified impurities: for each témoin avec une solution à 1 ppm de plomb (Pb) obtenue
impurity, not more than 0.5 times the area of the par
principal peak in the chromatogram obtained with dilution de la solution à 100 ppm de plomb (Pb) R avec du
reference solution (a) (0.05 per cent); méthanol R.
 — total: not more than twice the area of Perte à la dessiccation (2.2.32) : au maximum 0,5 pour
cent,
the principal peak in the chromatogram obtained
déterminé sous vide sur 1,000 g d’ibuprofène.
with reference solution (a) (0.2 per cent);
Cendres sulfuriques (2.4.14) : au maximum 0,1 pour cent,
 — disregard limit: 0.3 times the area of déterminé sur 1,0 g d’ibuprofène.
the principal peak in the chromatogram obtained
with reference solution (a) (0.03 per cent). DOSAGE
Dissolvez 0,450 g d’ibuprofène dans 50 mL de méthanol R.
Impurity F
Titrez par l’hydroxyde de sodium 0,1 M en présence
de 0,4 mL de solution de phénolphtaléine R1 jusqu’à virage
Gas chromatography (2.2.28): use the au rouge.
normalisation procedure. Effectuez un titrage à blanc.
1 mL d’hydroxyde de sodium 0,1 M correspond à 20,63 mg
Methylating solution  Dilute 1 mL of de C13H18O2.
IMPURETÉS
N,N-dimethylformamide dimethylacetal R and 1 mL
Impuretés spécifiées : A, F, J, N.
of pyridine R to 10 mL with ethyl acetate R.
Autres impuretés décelables (si elles sont présentes à une
teneur suffisante, les substances suivantes seront détectées
Test solution  Weigh about 50.0 mg of par
the substance to be examined into a sealable vial, l’un des essais de la monographie. Elles sont limitées par le
dissolve in 1.0 mL of ethyl acetate R, add 1 mL of critère général d’acceptation applicable aux autres
impuretés
the methylating solution, seal and heat at 100 °C in
ou impuretés non spécifiées, ou par les dispositions de la
a block heater for 20 min. Allow to cool. Remove
monographie générale Substances pour usage
the reagents under a stream of nitrogen at room pharmaceutique
temperature. Dissolve the residue in 5 mL of ethyl (2034). Il n’est donc pas nécessaire de les identifier pour
acetate R. démontrer la conformité de la substance. Voir également
chapitre 5.10. Contrôle des impuretés dans les substances
pour
Reference solution (a)  Dissolve 0.5 mg
usage pharmaceutique) : B, C, D, E, G, H, I, K, L,M, O, P,
of ibuprofen impurity F CRS in ethyl acetate R and
Q, R.
dilute to 10.0 mL with the same solvent. A. R1 = OH, R2 = CH2-CH(CH3)2, R3 = H : acide
(2RS)-2-[3-(2-méthylpropyl)phényl]propanoïque,
Reference solution (b)  Weigh about B. R1 = OH, R2 = H, R3 = [CH2]3-CH3 : acide
50.0 mg of ibuprofen CRS into a sealable vial, (2RS)-2-(4-butylphényl)propanoïque,
dissolve in 1.0 mL of reference solution (a), add 1 C. R1 = NH2, R2 = H, R3 = CH2-CH(CH3)2 : (2RS)-2-[4-(2-
mL of the methylating solution, seal and heat at méthylpropyl)phényl]propanamide,
100 °C in a block heater for 20 min. Allow to cool. D. R1 = OH, R2 = H, R3 = CH3 : acide (2RS)-2-(4-
Remove the reagents under a stream of nitrogen at méthylphényl)propanoïque,
room temperature. Dissolve the residue in 5 mL of E. 1-[4-(2-méthylpropyl)phényl]éthanone,
ethyl acetate R. F. acide 3-[4-(2-méthylpropyl)phényl]propanoïque,
G. acide (1RS,4RS)-7-(2-méthylpropyl)-1-[4-(2-
méthylpropyl)phényl]-1,2,3,4-tétrahydronaphtalène-1,
Column: 4-dicarboxylique,
 — material: fused silica; H. X = O : (3RS)-1,3-bis[4-(2-méthylpropyl)phényl]butan-
 — size: l = 25 m, Ø = 0.53 mm; 1-one,
I. X = H2 : 1-(2-méthylpropyl)-4-[(3RS)-3-[4-(2-
 — stationary phase: macrogol 20 000 R méthylpropyl)phényl]butyl]benzène,
(film thickness 2 µm). J. R = CO-CH(CH3)2 : acide (2RS)-2-[4-(2-
méthylpropanoyl)
phényl]propanoïque,
Carrier gas  helium for chromatography N. R = C2H5 : acide (2RS)-2-(4-éthylphényl)propanoïque
R.

Flow rate  5.0 mL/min.

Temperature:
 — column: 150 °C;
 — injection port: 200 °C;
 — detector: 250 °C.

Detection  Flame ionisation.

Injection  1 µL of the test solution and


reference solution (b).

Run time  Twice the retention time of


ibuprofen.

System suitability:
 — relative retention with reference to
ibuprofen (retention time = about 17 min): impurity
F = about 1.5.

Limit:
 — impurity F: maximum 0.1 per cent.

Heavy metals (2.4.8)

Maximum 10 ppm.

12 mL of solution S complies with test B.


Prepare the reference solution using lead standard
solution (1 ppm Pb) obtained by diluting lead
standard solution (100 ppm Pb) R with methanol R.

Loss on drying (2.2.32)

Maximum 0.5 per cent, determined on


1.000 g by drying in vacuo.
Sulfated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0


g.

ASSAY

Dissolve 0.450 g in 50 mL of methanol R.


Add 0.4 mL of phenolphthalein solution R1. Titrate
with 0.1 M sodium hydroxide until a red colour is
obtained. Carry out a blank titration.

1 mL of 0.1 M sodium hydroxide is


equivalent to 20.63 mg of C13H18O2.

IMPURITIES

Specified impurities  A, F, J, N

Other detectable impurities (the following


substances would, if present at a sufficient level,
be detected by one or other of the tests in the
monograph. They are limited by the general
acceptance criterion for other/unspecified impurities
and/or by the general monograph Substances for
pharmaceutical use (2034). It is therefore not
necessary to identify these impurities for
demonstration of compliance. See also 5.10.

Control of impurities in substances for


pharmaceutical use): B, C, D, E, G, H, I, K, L, M,
O, P, Q, R.

A. R1 = OH, R2 = CH2-CH(CH3)2, R3 = H: (2RS)-


2-[3-(2-methylpropyl)phenyl]propanoic acid,

B. R1 = OH, R2 = H, R3 = [CH2]3-CH3: (2RS)-2-(4-


butylphenyl)propanoic acid,

C. R1 = NH2, R2 = H, R3 = CH2-CH(CH3)2: (2RS)-


2-[4-(2-methylpropyl)phenyl]propanamide,

D. R1 = OH, R2 = H, R3 = CH3: (2RS)-2-(4-


methylphenyl)propanoic acid,

E. 1-[4-(2-methylpropyl)phenyl]ethanone,

F. 3-[4-(2-methylpropyl)phenyl]propanoic acid,

G. (1RS,4RS)-7-(2-methylpropyl)-1-[4-(2-
methylpropyl)phenyl]-1,2,3,4-
tetrahydronaphthalene-1,4-dicarboxylic acid,

H. X = O: (3RS)-1,3-bis[4-(2-
methylpropyl)phenyl]butan-1-

I. X = H2: 1-(2-methylpropyl)-4-[(3RS)-3-[4-(2-


methylpropyl)phenyl]butyl]benzene,

J. R = CO-CH(CH3)2: (2RS)-2-[4-(2-


methylpropanoyl)phenyl]propanoic acid, N. R =
C2H5: (2RS)-2-(4-ethylphenyl)propanoic acid,

 K. R = CHO: (2RS)-2-(4-


formylphenyl)propanoic acid,

 L. R = CHOH-CH(CH3)2: 2-[4-(1-


hydroxy-2-methylpropyl)phenyl]propanoic acid,

 O. R = CH(CH3)-C2H5: 2-[4-(1-


methylpropyl)phenyl]propanoic acid,

 M. R1 = OH, R2 = CH3, R3 = CO2H:


(2RS)-2-hydroxy-2-[4-(2-
methylpropyl)phenyl]propanoic acid,

 P. R1 = H, R2 = CH3, R3 = CH2OH:


(2RS)-2-[4-(2-methylpropyl)phenyl]propan-1-ol,

 Q. R1 = R2 = H, R3 = CH2OH: 2-[4-(2-


methylpropyl)phenyl]ethanol,

 R. 1,1¢-(ethane-1,1-diyl)-4,4¢-(2-
methylpropyl)dibenzene.

Ph Eur

USP Monographs: Ibuprofen


buprofen

(eye'' bue proe' fen).


C13H18O2 206.28

Benzeneacetic acid, -methyl-4-(2-methylpropyl), (±)-.


(±)-p-Isobutylhydratropic acid.
(±)-2-(p-Isobutylphenyl)propionic acid [15687-27-1].

(±) Mixture [58560-75-1].


» Ibuprofen contains not less than 97.0 percent and not more than 103.0 percent of
C13H18O2, calculated on the anhydrous basis.
Packaging and storage— Preserve in tight containers.

USP Reference standards 11 —

USP Ibuprofen RS

USP Ibuprofen Related Compound C RS

Identification—

A: Infrared Absorption 197M —Do not dry specimens.

B: Ultraviolet Absorption 197U —


Solution: 250 µg per mL.

Medium: 0.1 N sodium hydroxide.


Respective absorptivities at 264 nm and 273 nm, calculated on the anhydrous basis, do not
differ by more than 3.0%.

C: The chromatogram of the Assay preparation obtained as directed in the Assay exhibits
a major peak for ibuprofen, the retention time of which, relative to that of the internal
standard, corresponds to that exhibited in the chromatogram of the Standard preparation,
obtained as directed in the Assay.

Water, Method I 921 : not more than 1.0%.

Residue on ignition 281 : not more than 0.5%.


Delete the following:

Heavy metals, Method II 231 : 0.002%. (Official 1-Dec-2015)

Chromatographic purity—
Mobile phase— Prepare a suitable filtered mixture of water, previously adjusted with
phosphoric acid to a pH of 2.5 and acetonitrile (1340:680). Make adjustments if necessary

(see System Suitability under Chromatography 621 ).

Test preparation— Prepare a solution of Ibuprofen in acetonitrile containing about 5 mg


per mL.

Resolution solution— Prepare a solution in acetonitrile containing in each mL about 5 mg


of Ibuprofen and 5 mg of valerophenone.

Chromatographic system (see Chromatography 621 )— The liquid chromatograph is


equipped with a 214-nm detector and a 4-mm × 15-cm column that contains 5-µm packing

L1 and is maintained at 30 ± 0.5 . The flow rate is about 2 mL per minute. Chromatograph
a series of 5-µL injections of the Test preparation to condition the column. Chromatograph
the Resolution solution, and record the peak responses as directed for Procedure: the
relative retention times are about 0.8 for valerophenone and 1.0 for ibuprofen, and the
resolution, R, between the valerophenone peak and the ibuprofen peak is not less than
2.0.

Procedure— [note—Use peak areas where peak responses are indicated. ] Inject about 5
µL of the Test preparation into the chromatograph, record the chromatogram, and
measure the peak responses. Calculate the percentage of each impurity taken by the
formula:
100ri / rt

in which ri is the response of an individual peak, other than the solvent peak and the main
ibuprofen peak, and rt is the sum of the responses of all the peaks, excluding that of the
solvent peak: not more than 0.3% of any individual impurity is found, and the sum of all the
individual impurities found does not exceed 1.0%.

Limit of ibuprofen related compound C— Using the chromatograms of the Assay


preparation and the Ibuprofen related compound C standard solution, obtained as directed
in the Assay, calculate the percentage of ibuprofen related compound C (C12H16O) in the
portion of Ibuprofen taken by the formula:
10,000(C / W)(RU / RS)

in which C is the concentration, in mg per mL, of USP Ibuprofen Related Compound C RS


in the Ibuprofen related compound C standard solution; W is the weight, in mg, of
Ibuprofen taken to prepare the Assay preparation; and RU and RS are the peak response
ratios of ibuprofen related compound C to valerophenone obtained from the Assay
preparation and the Ibuprofen related compound C standard solution, respectively: not
more than 0.1% is found.

Assay—
Mobile phase— Dissolve 4.0 g of chloroacetic acid in 400 mL of water, and adjust with
ammonium hydroxide to a pH of 3.0. Add 600 mL of acetonitrile, filter, and degas. Make

adjustments if necessary (see System Suitability under Chromatography 621 ).

Internal standard solution— Prepare a solution of valerophenone in Mobile phase having a


concentration of about 0.35 mg per mL.

Standard preparation— Dissolve an accurately weighed quantity of USP Ibuprofen RS in


Internal standard solution to obtain a solution having a known concentration of about 12
mg per mL.

Ibuprofen related compound C standard solution— Quantitatively dissolve an accurately


weighed quantity of USP Ibuprofen Related Compound C RS in acetonitrile to obtain a
solution having a known concentration of about 0.6 mg per mL. Add 2.0 mL of this stock
solution to 100.0 mL of Internal standard solution, and mix to obtain a solution having a
known concentration of about 0.012 mg of ibuprofen related compound C per mL.

Assay preparation— Transfer about 1200 mg of Ibuprofen, accurately weighed, to a 100-


mL volumetric flask, dilute with Internal standard solution to volume, and mix.

Chromatographic system (see Chromatography 621 )— The liquid chromatograph is


equipped with a 254-nm detector and a 4.6-mm × 25-cm column that contains packing L1.
The flow rate is about 2 mL per minute. Chromatograph the Standard preparation, and
record the peak responses as directed for Procedure: the relative retention times are about
1.4 for the internal standard and 1.0 for ibuprofen; the resolution, R, between ibuprofen
and the internal standard is not less than 2.5; and the relative standard deviation for
replicate injections is not more than 2.0%. Chromatograph the Ibuprofen related
compound C standard solution, and record the peak responses as directed for Procedure:
the relative retention times are about 1.0 for valerophenone and 1.2 for ibuprofen related
compound C; the resolution, R, between valerophenone and ibuprofen related compound
C is not less than 2.5; the tailing factors for the individual peaks are not more than 2.5; and
the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 5 µL) of the Standard preparation, the
Assay preparation, and the Ibuprofen related compound C standard solution into the
chromatograph, record the chromatograms, and measure the responses for the major
peaks. Calculate the quantity, in mg, of C13H18O2 in the portion of Ibuprofen taken by the
formula:
100C(RU / RS)

in which C is the concentration, in mg per mL, of USP Ibuprofen RS in the Standard


preparation; and RU and RS are the peak response ratios obtained from the Assay
preparation and the Standard preparation, respectivel

USP Monographs: Ibuprofen Tablets


buprofen Tablets
» Ibuprofen Tablets contain not less than 90.0 percent and not more than 110.0 percent of
the labeled amount of C13H18O2.
Packaging and storage— Preserve in well-closed containers.

Labeling— Where the Tablets are gelatin-coated, the label so states.

USP Reference standards 11 —

USP Ibuprofen RS

USP Ibuprofen Related Compound C RS

Identification—
A: Grind 1 Tablet to a fine powder in a mortar, add about 5 mL of chloroform, and swirl.
Filter the mixture, and evaporate the filtrate with the aid of a stream of nitrogen to dryness:
the IR absorption spectrum of a mineral oil dispersion of the residue so obtained exhibits
maxima only at the same wavelengths as that of a similar preparation of USP Ibuprofen
RS.

B: Its retention time, relative to that of the internal standard, determined as directed in the
Assay, corresponds to that of USP Ibuprofen RS.

Dissolution 711 —
Medium: pH 7.2 phosphate buffer (see under Buffers in the section Reagents, Indicators,
and Solutions); 900 mL.

Apparatus 2: 50 rpm.

Time: 60 minutes.

Procedure— Determine the amount of C13H18O2 dissolved from UV absorbances at the


wavelength of maximum absorbance at about 221 nm of filtered portions of the solution
under test, suitably diluted with Dissolution Medium, if necessary, in comparison with a
Standard solution having a known concentration of USP Ibuprofen RS in the same
medium. [note—Where the Tablets are labeled as gelatin-coated, determine the amount of
C13H18O2 dissolved from the UV absorbance at the wavelength of maximum absorbance
at about 266 nm from which is subtracted the absorbance at 280 nm, in comparison with
the Standard solution similarly measured. ]

Tolerances— Not less than 80% (Q) of the labeled amount of C13H18O2 is dissolved in
60 minutes.

Uniformity of dosage units 905 : meet the requirements.

Water, Method I 921 : not more than 5.0%, except that Tablets labeled as gelatin-
coated are exempt from this requirement.

Limit of ibuprofen related compound C— Using the chromatograms of the Assay


preparation and the Ibuprofen related compound C standard solution obtained as directed
in the Assay, calculate the percentage of ibuprofen related compound C (C12H16O) in the
Tablets taken by the formula:
10,000C(A / WI)(RU / RS)

in which C is the concentration, in mg per mL, of USP Ibuprofen Related Compound C RS


in the Ibuprofen related compound C standard solution; A is the average weight, in mg, of
a Tablet; W is the weight of Tablet powder taken to prepare the Assay preparation; I is the
quantity, in mg, of ibuprofen per Tablet as obtained in the Assay; and RU and RS are the
ratios of the ibuprofen related compound C peak response to the valerophenone peak
response obtained from the Assay preparation and the Standard preparation, respectively:
not more than 0.25% per Tablet is found.

Assay—
Mobile phase, Internal standard solution, and Standard preparation— Prepare as directed
in the Assay under Ibuprofen.

Ibuprofen related compound C standard solution— Quantitatively dissolve an accurately


weighed quantity of USP Ibuprofen Related Compound C RS in acetonitrile to obtain a
stock solution having a known concentration of about 0.6 mg per mL. Add 2.0 mL of this
stock solution to 100 mL of Internal standard solution, and mix.

Assay preparation— Weigh and finely powder not fewer than 20 Tablets. Transfer an
accurately weighed portion of the powder, equivalent to about 1200 mg of ibuprofen, to a
suitable container, add 100.0 mL of Internal standard solution, and shake for 10 minutes.
[note—Where the Tablets are coated, place an accurately counted number of Tablets,
equivalent to not less than 1200 mg of ibuprofen, in a container, add an accurately
measured volume of Internal standard solution, sufficient to obtain an Assay preparation
containing about 12 mg of ibuprofen per mL, and about 15 glass beads, and shake until
the Tablets are completely disintegrated. ] Centrifuge a portion of the suspension so
obtained and use the clear supernatant as the Assay preparation.

Chromatographic system (see Chromatography 621 )—The liquid chromatograph is


equipped with a 254-nm detector and a 4.6-mm × 25-cm column that contains packing L1.
The flow rate is about 2 mL per minute. Chromatograph the Standard preparation, and
record the peak responses as directed for Procedure: the relative retention times are about
0.75 for ibuprofen and 1.0 for valerophenone; the resolution, R, between ibuprofen and
valerophenone is not less than 2.5; the tailing factors for the individual peaks are not more
than 2.5; and the relative standard deviation for replicate injections is not more than 2.0%.
Chromatograph the Ibuprofen related compound C standard solution, and record the peak
responses as directed for Procedure: the relative retention times are about 1.0 for
valerophenone and 1.2 for ibuprofen related compound C; the resolution, R, between
valerophenone and ibuprofen related compound C is not less than 2.5; the tailing factors
for the individual peaks are not more than 2.5; and the relative standard deviation for
replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 5 µL) of the Standard preparation, the
Assay preparation, and the Ibuprofen related compound C standard solution into the
chromatograph, record the chromatograms, and measure the responses for the major
peaks. Calculate the quantity, in mg, of ibuprofen (C13H18O2) in each Tablet taken by the
formula:
100C(A / W)(RU / RS)

in which C is the concentration, in mg per mL, of USP Ibuprofen RS in the Standard


preparation; A is the average weight, in mg, of a Tablet; W is the weight, in mg, of Tablet
powder taken to prepare the Assay preparation; and RU and RS are the ratios of the
ibuprofen peak response to the valerophenone peak response obtained from the Assay
preparation and the Standard preparation, respectively; or where intact Tablets were
taken, calculate the quantity, in mg, of C13H18O2 in each Tablet taken by the formula:
(CV/N)(RU / RS)

in which V is the volume, in mL, of Internal standard solution used to prepare the Assay
preparation; N is the number of Tablets taken; and the other terms are as defined above.

BP monograph Ibuprofen Tablets


Action and use

Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.

DEFINITION

Ibuprofen Tablets contain Ibuprofen. They are coated.

The tablets comply with the requirements stated under Tablets and with the following requirements.

Content of ibuprofen, C13H18O2

95.0 to 105.0% of the stated amount.

IDENTIFICATION

 A. Extract a quantity of the powdered tablets containing 0.5 g of Ibuprofen with 20 mL of


acetone, filter and evaporate the filtrate to dryness in a current of air without heating. The infrared absorption
spectrum of the residue, Appendix II A, is concordant with the reference spectrum of ibuprofen (RS 186).
 B. Melting point of the residue obtained in test A, after recrystallisation from petroleum spirit
(boiling range, 40° to 60°), about 75°, Appendix V A.

TEST

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

 (1) Add 30 mL of methanol to a quantity of the powdered tablets containing 0.2 g of Ibuprofen,


shake for 30 minutes, add 30 mL of methanol and sufficient water to produce 100 mL, mix and filter through
a glass microfibre filter paper (Whatman GF/C is suitable).

 (2) Dilute 1 volume of solution (1) to 100 volumes with the mobile phase.

 (3) Dissolve 50 mg of ibuprofen BPCRS in 2.5 mL of a 0.006% w/v solution of ibuprofen impurity


B BPCRS in methanol (prepared by diluting 1 volume of ibuprofen impurity B BPCRS to 10 volumes with
methanol ) and add sufficient methanol to produce 25 mL.

CHROMATOGRAPHIC CONDITIONS

 (a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica
gel for chromatography (5 µm) (Spherisorb ODS 2 is suitable).

 (b) Use isocratic elution and the mobile phase described below.

 (c) Use a flow rate of 2 mL per minute.

 (d) Use an ambient column temperature.

 (e) Use a detection wavelength of 214 nm.

 (f) Inject 20 µL of each solution.

 (g) Equilibrate the column with the mobile phase for about 45 minutes before starting the
chromatography.

 (h) Allow the chromatography to proceed for 1.5 times the retention time of the principal peak.
When the chromatograms are recorded under the conditions described above, the retention time of ibuprofen
is about 20 minutes.

MOBILE PHASE

0.5 volume of orthophosphoric acid , 340 volumes of acetonitrile and 600 volumes of water diluted
to 1000 volumes with water after equilibration.

SYSTEM SUITABILITY

In the chromatogram obtained with solution (3) measure the height (a) of the peak due to 2-(4-
butylphenyl)-propionic acid and the height (b) of the lowest point of the curve separating this peak from that
due to ibuprofen. The test is not valid unless a is greater than 1.5b. If necessary, adjust the concentration of
acetonitrile in the mobile phase to obtain the required resolution.

LIMITS

In the chromatogram obtained with solution (1):


the area of any peak corresponding to ibuprofen impurity B is not greater than the area of the
corresponding peak in the chromatogram obtained with solution (3) (0.3%);

the area of any other secondary peak is not greater than 0.3 times the area of the principal peak in
the chromatogram obtained with solution (2) (0.3%);

the sum of the area of any secondary peaks, other than the peak due to impurity B, is not greater
than 0.7 times the area of the principal peak in the chromatogram obtained with solution (2) (0.7%).

Disregard any peak the area of which is less than 0.1 times the area of the principal peak in the
chromatogram obtained with solution (2) (0.1%).

ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D,
using the following solutions.

 (1) Shake a quantity of the powdered tablets containing 0.2 g of Ibuprofen with 30 mL of the
mobile phase for 30 minutes, add sufficient of the mobile phase to produce 100 mL and mix thoroughly.
Centrifuge 25 mL of the solution at 2500 g for 5 minutes and use the supernatant liquid.

 (2) 0.2% w/v of ibuprofen BPCRS in the mobile phase.

CHROMATOGRAPHIC CONDITIONS

 (a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped octadecylsilyl silica
gel for chromatography (10 µm) (Nucleosil C18 is suitable).

 (b) Use isocratic elution and the mobile phase described below.

 (c) Use a flow rate of 1.5 mL per minute.

 (d) Use an ambient column temperature.

 (e) Use a detection wavelength of 264 nm.

 (f) Inject 20 µL of each solution.

MOBILE PHASE

3 volumes of orthophosphoric acid , 247 volumes of water and 750 volumes of methanol .

DETERMINATION OF CONTENT

Calculate the content of C13H18O2 using the declared content of C13H18O2 in ibuprofen BPCRS.

IMPURITIES

The impurities limited by the requirements of this monograph include:

1. (2RS)-2-(4-butylphenyl)propanoic acid (Ibuprofen Impurity B).

CONCLUSION:
L’analyse du médicament (matière première ou produit fini) est
réglementée. Elle passe par un protocole stricte appelé
monographie retrouvées dans les pharmacopées
Pour une matière première, les monographies des différentes
pharmacopées présentent quasiment les mêmes protocoles :
1- Identification :
Principale méthode : spectroscopie infra-rouge
2- Essais
Point essentiel : substances apparentées avec comme
principale méthode : Chromatographie en phase liquide
HPLC
3- Dosage
Titrimétrie ou potentiométrie

Pour un produit fini, la principale méthode d’analyse est


Chromatographie en phase liquide HPLC