硫酸氢氯吡格雷最新欧洲药典

04/2011:2531 CLOPIDOGREL HYDROGEN SULFATE
Clopidogreli hydrogenosulfas
C
16H
18
ClNO
6
S
2
M
r
419.9
[120202-66-6]
DEFINITION
Methyl (2S)-(2-chlorophenyl)[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate sulfate.
Content: 99.0 per cent to 101.0 per cent (anhydrous substance).
CHARACTERS
Appearance: white or almost white powder.
Solubility: freely soluble in water and in methanol, practically insoluble in cyclohexane.
It shows polymorphism (5.9).
IDENTIFICATION
Carry out either tests A, B, D or tests B, C, D.
A.Specific optical rotation (2.2.7): + 54.0 to + 58.0 (anhydrous substance).
Dissolve 0.250 g in methanol R and dilute to 25.0 mL with the same solvent.
B.Infrared absorption spectrophotometry (2.2.24).
Comparison: clopidogrel hydrogen sulfate CRS.
If the spectra obtained show differences, dissolve the substance to be examined and the reference substance separately in anhydrous ethanol R, evaporate to dryness and record new spectra using the residues (the substance may stick to the surface of the recipient used).
C.Enantiomeric purity (see Tests).
D.It gives reaction (a) of sulfates (2.3.1).
TESTS
Appearance of solution. The solution is clear (2.2.1) and not more intensely coloured than reference solution Y
6
(2.2.2, Method I).
Dissolve 1.0 g in methanol R and dilute to 20.0 mL with the same solvent.
Enantiomeric purity. Liquid chromatography (2.2.29): use the normalisation procedure.
Test solution. Dissolve 0.1 g of the substance to be examined in 25.0 mL of anhydrous ethanol R and dilute to 50.0 mL with heptane R.
Reference solution. Dissolve 10 mg of clopidogrel for system suitability CRS(containing impurities B and C) in 2.5 mL of anhydrous ethanol R and dilute to 5.0 mL with heptane R.
Column:
—size: l = 0.25 m, Ø = 4.6 mm;
—stationary phase: silica gel OJ for chiral separations R (10 µm).
Mobile phase: anhydrous ethanol R, heptane R (15:85 V/V).
Flow rate: 0.8 mL/min.
Detection: spectrophotometer at 220 nm.
Injection: 10 µL.
Run time: 1.25 times the retention time of clopidogrel.
Identification of impurities: use the chromatogram supplied with clopidogrel for system suitability CRS and the chromatogram obtained with the reference solution to identify the peaks due to impurities B and C.
Relative retention with reference to clopidogrel (retention time = about 18 min): impurity C = about 0.6; impurity B = about 0.7.
System suitability: reference solution:
—resolution: minimum 2.0 between the peaks due to impurities C and B;
—signal-to-noise ratio: minimum 20 for the peak due to impurity C.
Limit:
—impurity C: maximum 0.5 per cent.
Related substances. Liquid chromatography (2.2.29).
Solvent mixture: mobile phase A, acetonitrile R1 (40:60 V/V).
Test solution. Dissolve 65 mg of the substance to be examined in the solvent mixture and dilute to 10.0 mL with the solvent mixture.
Reference solution (a). Dissolve 5 mg of clopidogrel impurity A CRS in the solvent mixture and dilute to
25.0 mL with the solvent mixture.
Reference solution (b). Dissolve 32 mg of clopidogrel for system suitability CRS (containing impurities B
and C) in the solvent mixture, add 0.5 mL of reference solution (a) and dilute to 5.0 mL with the solvent mixture.
Reference solution (c). Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.
Column:
—size: l = 0.15 m, Ø = 3.9 mm;
—stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 µm);
—temperature: 30 °C.
Mobile phase:
—mobile phase A: mix 5 volumes of methanol R2 and 95 volumes of a 0.96 g/L solution of sodium pentanesulfonate monohydrate R adjusted to pH 2.5 with phosphoric acid R;
—mobile phase B: methanol R2, acetonitrile R1 (5:95 V/V);
Time (min)Mobile phase A
(per cent V/V)
Mobile phase B
(per cent V/V)
0 - 389.510.5
3 - 4889.5 → 31.510.5 → 68.5
Flow rate : 1.0 mL/min.
Detection : spectrophotometer at 220 nm.
Injection : 10 µL of the test solution and reference solutions (b) and (c).
Identification of impurities : use the chromatogram supplied with clopidogrel for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities A and B. Relative retention with reference to clopidogrel (retention time = about 25 min): impurity A = about 0.4; impurity B = about 1.1.
System suitability : reference solution (b):
— peak-to-valley ratio : minimum 10, where H p = height above the baseline of the peak due to impurity B and H v = height above the baseline of the lowest point of the curve separating this peak from the peak due to clopidogrel.
Limits :
— impurity B : not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.3 per cent);
— impurity A : not more than twice the area of the principal peak in the chromatogram obtained with reference solution (c) (0.2 per cent);
— unspecified impurities : for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (c) (0.10 per cent);
— total : not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.5 per cent);
— disregard limit : 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.05 per cent).
Heavy metals (2.4.8): maximum 20 ppm.
1.0 g complies with test C. Prepare the reference solution using 2 mL of lead standard solution (10 ppm Pb) R.
Water (2.5.12): maximum 0.5 per cent, determined on 1.00 g. Replace the solvent after each titration.
Sulfated ash (2.4.14): maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Dissolve 0.160 g in a mixture of 10 mL of acetone R, 10 mL of methanol R and 30 mL of water R. Titrate with 0.1 M sodium hydroxide, determining the end-point potentiometrically (2.2.20). A precipitate may be formed during the titration.
1 mL of 0.1 M sodium hydroxide is equivalent to 20.99 mg of C 16H 18ClNO 6S 2.
STORAGE
Protected from light.
IMPURITIES
Specified impurities: A, B, C.
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 ): D. 48 - 68 31.5 68.5
A.(2S)-(2-chlorophenyl)[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetic acid,
B.methyl (2S)-(2-chlorophenyl)[4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl]acetate,
C.methyl (2R)-(2-chlorophenyl)[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate,
D.methyl (2R)-(2-chlorophenyl)[(2S)-(2-chlorophenyl)[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetyloxy]
acetate.。