Tranexamic acid EUROPEAN PHARMACOPOEIA 7.0
A. R = CH3: (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-(methoxycarbonyl)-
3-phenylpropyl]amino]propanoyl]octahydro-1H-indole-2-
carboxylic acid (methyl ester derivative),
B. R = CH(CH3)2 : (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-[(1-methyl-
ethoxy)carbonyl]-3-phenylpropyl]amino]propanoyl]octa-
hydro-1H-indole-2-carboxylic acid (isopropyl ester derivative),
E. R = H: (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-1-carboxy-3-
phenylpropyl]amino]propanoyl]octahydro-1H-indole-2-
carboxylic acid (trandolaprilate),
C. (2S,3aR,7aS)-1-[(2S)-2-[[(1S)-3-cyclohexyl-1-
(ethoxycarbonyl)propyl]amino]propanoyl]octahydro-
1H-indole-2-carboxylic acid (hexahydrotrandolapril),
D. ethyl (2S)-2-[(3S,5aS,9aR,10aS)-3-methyl-1,4-
dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl]-4-
phenylbutanoate (trandolapril diketopiperazine),
F. (2R,3aR,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-
phenylpropyl]amino]propanoyl]octahydro-1H-indole-2-
carboxylic acid.
01/2008:0875
corrected 6.0
TRANEXAMIC ACID
Acidum tranexamicum
C8H15NO2 Mr 157.2
[1197-18-8]
DEFINITION
trans-4-(Aminomethyl)cyclohexanecarboxylic acid.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : freely soluble in water and in glacial acetic acid,
practically insoluble in acetone and in ethanol (96 per cent).
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Preparation : discs.
Comparison : tranexamic acid CRS.
TESTS
pH (2.2.3) : 7.0 to 8.0.
Dissolve 2.5 g in carbon dioxide-free water R and dilute to
50 mL with the same solvent.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 0.20 g of the substance to be examined
in water R and dilute to 20.0 mL with the same solvent.
Reference solution (a). Dilute 5.0 mL of the test solution
to 100.0 mL with water R. Dilute 1.0 mL of this solution to
10.0 mL with water R.
Reference solution (b). Dissolve 20 mg of tranexamic acid CRS
(containing impurity C) in water R and dilute to 2 mL with the
same solvent.
Reference solution (c). Dissolve 12 mg of 4-aminomethylben-
zoic acid R (impurity D) in water R and dilute to 100 mL with
the same solvent. Dilute 1 mL of the solution to 50 mL with
water R. Dilute 5 mL of this solution to 200 mL with water R.
Column :
— size : l = 0.25 m, Ø = 4.6 mm or l = 0.25 m, Ø = 6.0 mm;
— stationary phase : octadecylsilyl silica gel for
chromatography R (5 μm).
Mobile phase : dissolve 11.0 g of anhydrous sodium dihydrogen
phosphate R in 500 mL of water R and add 5 mL of
triethylamine R and 1.4 g of sodium laurilsulfate R. Adjust to
pH 2.5 with dilute phosphoric acid R and dilute to 600 mL with
water R. Add 400 mL of methanol R and mix.
Flow rate : 0.9 mL/min.
Detection : spectrophotometer at 220 nm.
Injection : 20 μL.
Run time : 3 times the retention time of tranexamic acid.
Identification of impurities : use the chromatogram supplied
with tranexamic acid CRS and the chromatogram obtained with
reference solution (b) to identify the peak due to impurity C ;
use the chromatogram obtained with reference solution (c) to
identify the peak due to impurity D.
Relative retention with reference to tranexamic acid (retention
time = about 13 min) : impurity C = about 1.1 ; impurity D = about
1.3 ; impurity B = about 1.5 ; impurity A = about 2.1.
System suitability : reference solution (b) :
— resolution : minimum 1.5 between the peaks due to
tranexamic acid and impurity C.
Limits :
— correction factors : for the calculation of content, multiply the
peak areas of the following impurities by the corresponding
correction factor : impurity B = 1.2 ; impurity C = 0.005 ;
impurity D = 0.006 ;
— impurity A : not more than 0.2 times the area of the
principal peak in the chromatogram obtained with reference
solution (a) (0.1 per cent) ;
— impurity B : not more than 0.4 times the area of the
principal peak in the chromatogram obtained with reference
solution (a) (0.2 per cent) ;
— unspecified impurities : for each impurity, not more than
0.2 times the area of the principal peak in the chromatogram
obtained with reference solution (a) (0.10 per cent) ;
— sum of unspecified impurities : not more than 0.4 times the
area of the principal peak in the chromatogram obtained
with reference solution (a) (0.2 per cent) ;
— disregard limit : 0.05 times the area of the principal peak
in the chromatogram obtained with reference solution (a)
(0.025 per cent).
3122 See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 7.0 Trapidil
Halides expressed as chlorides (2.4.4) : maximum 140 ppm.
Dissolve 1.2 g in water R and dilute to 50 mL with the same
solvent.
Heavy metals (2.4.8) : maximum 10 ppm.
Dissolve 2.0 g in water R and dilute to 20 mL with the same
solvent. 12 mL of this solution complies with test A. Prepare the
reference solution using lead standard solution (1 ppm Pb) R.
Loss on drying (2.2.32) : maximum 0.5 per cent, determined on
1.000 g by drying in an oven at 105 °C for 2 h.
Sulfated ash (2.4.14) : maximum 0.1 per cent, determined on
1.0 g.
ASSAY
Dissolve 0.140 g in 20 mL of anhydrous acetic acid R.
Titrate with 0.1 M perchloric acid, determining the end-point
potentiometrically (2.2.20).
1 mL of 0.1 M perchloric acid is equivalent to 15.72 mg of
C8H15NO2.
IMPURITIES
Specified impurities : A, B.
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) : C, D.
A. trans,trans-4,4′-(iminodimethylene)di(cyclohexanecarboxylic)
acid,
B. cis-4-(aminomethyl)cyclohexanecarboxylic acid,
C. (RS)-4-(aminomethyl)cyclohex-1-enecarboxylic acid,
D. 4-aminomethylbenzoic acid.
01/2008:1576
TRAPIDIL
Trapidilum
C10H15N5 Mr 205.3
[15421-84-8]
DEFINITION
N,N-Diethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine.
Content : 99.0 per cent to 101.0 per cent (dried substance).
CHARACTERS
Appearance : white or almost white, crystalline powder.
Solubility : freely soluble in water, soluble in ethanol and in
methylene chloride.
mp: about 102 °C.
IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).
Comparison : trapidil CRS.
TESTS
Solution S. Dissolve 2.0 g in carbon dioxide-free water R and
dilute to 100 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 0.2 mL of
methyl red solution R and 0.2 mL of 0.01 M hydrochloric acid.
The solution is red. Add 0.4 mL of 0.01 M sodium hydroxide.
The solution is yellow.
Related substances. Liquid chromatography (2.2.29).
Test solution. Dissolve 20.0 mg of the substance to be examined
in the mobile phase and dilute to 10.0 mL with the mobile phase.
Reference solution (a). Dissolve 5.0 mg of trapidil
impurity A CRS in the mobile phase and dilute to 50.0 mL with
the mobile phase. Dilute 1.0 mL of the solution to 50.0 mL with
the mobile phase.
Reference solution (b). Dissolve 5.0 mg of trapidil
impurity B CRS in the mobile phase and dilute to 50.0 mL with
the mobile phase. Dilute 1.0 mL of the solution to 50.0 mL with
the mobile phase.
Reference solution (c). Mix equal volumes of reference
solution (a) and reference solution (b).
Column :
— size : l = 0.125 m, Ø = 4.0 mm,
— stationary phase : base-deactivated octadecylsilyl silica gel
for chromatography R (5 μm),
Mobile phase : 50 mL of methanol R, 75 mL of acetonitrile R
and 800 mL of a 1.7 g/L solution of potassium dihydrogen
phosphate R adjusted to pH 2.45 with phosphoric acid R ;
dilute to 1000 mL with water R.
Flow rate : 1.0 mL/min.
Detection : spectrophotometer at 205 nm.
Injection : 10 μL.
Run time : 3 times the retention time of trapidil.
System suitability :
— resolution : minimum of 4.0 between the peaks due to
impurity A and impurity B in the chromatogram obtained
with reference solution (c).
General Notices (1) apply to all monographs and other texts 3123
2_Volume2_E.pdf
45-T-E
toc
Tranexamic acid
Acidum tranexamicum
DEFINITION
CHARACTERS
IDENTIFICATION
TESTS
pH (2.2.3): 7.0 to 8.0.
Related substances. Liquid chromatography (2.2.29).
Halides expressed as chlorides (2.4.4): maximum 140 ppm.
Heavy metals (2.4.8): maximum 10 ppm.
Loss on drying (2.2.32): maximum 0.5 per cent, determined on 1.0
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g
ASSAY
IMPURITIES
Trapidil
Trapidilum
DEFINITION
CHARACTERS
IDENTIFICATION
TESTS
Solution S. Dissolve 2.0 g in carbon dioxide-free water R and di
Appearance of solution. Solution S is clear (2.2.1) and colourle
Acidity or alkalinity. To 10 mL of solution S add 0.2 mL of meth
Related substances. Liquid chromatography (2.2.29).
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