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l18089640 发表于 2015-12-16 09:50:15 | 只看该作者回帖奖励

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哪位大侠能帮我找到德国的卡巴拉汀原料和贴剂的标准，还有英国卡巴拉汀原料标准，谢谢啦！

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工作QQ1 发表于 2015-12-17 18:31:04 | 只看该作者

Rivastigmine
European Union chaplet of stars
General Notices
(Ph. Eur. monograph 2629)

bp2013_v2_13_medicinal_and_pharmaceutical_substances_16 rivastigmine_1_2014_76_cs.png

C14H22N2O2    250.3 123441-03-2

Action and use
Cholinesterase inhibitor; treatment of Alzheimer's disease.

Ph Eur

DEFINITION
3-[(1S)-1-(Dimethylamino)ethyl]phenyl ethyl(methyl)carbamate.

Content
98.0 per cent to 102.0 per cent (anhydrous substance).

CHARACTERS
Appearance
Viscous, clear, colourless or yellow or very slightly brown, hygroscopic liquid.

Solubility
Sparingly soluble in water, very soluble in anhydrous ethanol and in heptane.

IDENTIFICATION
Carry out either tests A, B or tests B, C.

A. Specific optical rotation (2.2.7): -44.0 to -38.0 (anhydrous substance). Prepare the solution immediately before use.

Dissolve 0.300 g in ethyl acetate R and dilute to 50.0 mL with the same solvent.

B. Infrared absorption spectrophotometry (2.2.24).

Preparation  Film.

Comparison  rivastigmine hydrogen tartrate CRS, treated as follows: dissolve 0.100 g in 30 mL of buffer solution pH 11 R, then add 30 mL of 1,1-dimethylethyl methyl ether R and shake vigorously for 2 min. Allow the layers to separate. Filter the upper organic layer through anhydrous sodium sulfate R. Evaporate the filtrate under reduced pressure at a temperature not exceeding 60 °C to obtain a residue. Record the reference spectrum using this residue.

C. Enantiomeric purity (see Tests).

TESTS
Enantiomeric purity
Liquid chromatography (2.2.29).

Solution A  Solution containing 1.78 g/L of disodium hydrogen phosphate dihydrate R and 1.38 g/L of sodium dihydrogen phosphate monohydrate R. Adjust to pH 6.0 with phosphoric acid R.

Test solution  Dissolve 25.0 mg of the substance to be examined in the mobile phase and dilute to 100.0 mL with the mobile phase. Dilute 5.0 mL of the solution to 20.0 mL with the mobile phase.

Reference solution (a)  Dissolve 2.0 mg of rivastigmine impurity D CRS in the mobile phase and dilute to 200.0 mL with the mobile phase. Dilute 1.0 mL of the solution to 100.0 mL with the mobile phase.

Reference solution (b)  Dissolve 1 mg of rivastigmine hydrogen tartrate CRS in reference solution (a) and dilute to 10 mL with reference solution (a).

Column:
— size: l = 0.10 m, Ø = 4.0 mm;
— stationary phase: silica gel AGP for chiral chromatography R (5 μm).
Mobile phase  Mix 205 μL of N,N-dimethyloctylamine R and 20.0 mL of acetonitrile R1 and dilute to 1000 mL with solution A.

Flow rate  0.5 mL/min.

Detection  Spectrophotometer at 200 nm.

Injection  20 μL.

Run time  Twice the retention time of rivastigmine.

Relative retention  With reference to rivastigmine (retention time = about 9 min): impurity D = about 0.8.

System suitability  Reference solution (b):

— peak-to-valley ratio: minimum 2.5, where Hp = height above the baseline of the peak due to impurity D and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to rivastigmine.
Calculation of percentage content:
— use the concentration of impurity D in reference solution (a).
Limit:
— impurity D: maximum 0.3 per cent.
Related substances
Liquid chromatography (2.2.29). Carry out the test protected from light.

Test solution  Dissolve 62.5 mg of the substance to be examined in the mobile phase and dilute to 100.0 mL with the mobile phase.

Reference solution (a)  Dilute 1.0 mL of the test solution to 100.0 mL with the mobile phase. Dilute 1.0 mL of this solution to 10.0 mL with the mobile phase.

Reference solution (b)  Dissolve the contents of a vial of rivastigmine for system suitability CRS (containing impurities A, B and C) in 1.0 mL of the mobile phase.

Reference solution (c)  Dissolve 50.0 mg of rivastigmine hydrogen tartrate CRS in the mobile phase and dilute to 50.0 mL with the mobile phase.

Column:
— size: l = 0.25 m, Ø = 4.0 mm;
— stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 μm);
— temperature: 40 °C.
Mobile phase  Mix 42 volumes of an 8.9 g/L solution of disodium hydrogen phosphate dihydrate R previously adjusted to pH 7.0 with phosphoric acid R and 58 volumes of methanol R1.

Flow rate  1.0 mL/min.

Detection  Spectrophotometer at 214 nm.

Injection  20 μL of the test solution and reference solutions (a) and (b).

Run time  Twice the retention time of rivastigmine.

Identification of impurities  Use the chromatogram supplied with rivastigmine for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities A, B and C.

Relative retention  With reference to rivastigmine (retention time = about 10 min): impurity A = about 0.4; impurity C = about 0.6; impurity B = about 0.7.

System suitability  Reference solution (b):

— resolution: minimum 2.0 between the peaks due to impurities C and B.
Calculation of percentage contents:
— for each impurity, use the concentration of rivastigmine in reference solution (a).
Limits:
— impurity A: maximum 0.3 per cent;
— impurity B: maximum 0.15 per cent;
— unspecified impurities: for each impurity, maximum 0.10 per cent;
— total: maximum 0.5 per cent;
— reporting threshold: 0.05 per cent.
Heavy metals (2.4.8)
Maximum 20 ppm.

Solvent mixture  water R, acetone R (20:80 V/V).

0.250 g complies with test H. Prepare the reference solution using 0.5 mL of lead standard solution (10 ppm Pb) R.

Water (2.5.12)
Maximum 0.5 per cent, determined on 1.000 g.

Change the solvent after standardisation of the titrant and after every 3rd sample.

Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.

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

Injection  Test solution and reference solution (c).

System suitability  Reference solution (c):

— symmetry factor: maximum 2.5 for the peak due to rivastigmine.
Calculate the percentage content of C14H22N2O2 taking into account the assigned content of rivastigmine hydrogen tartrate CRS and a conversion factor of 0.625.

STORAGE
Under an inert gas, in an airtight container, protected from light, at a temperature of 2 °C to 8 °C.

IMPURITIES
Specified impurities A, B, D.

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.

bp2013_v2_13_medicinal_and_pharmaceutical_substances_16 rivastigmine_2_2014_76_cs.png

A. 3-[(1S)-1-(dimethylamino)ethyl]phenol (dimetol),

bp2013_v2_13_medicinal_and_pharmaceutical_substances_16 rivastigmine_3_2014_76_cs.png

B. 3-[(1S)-1-(dimethylamino)ethyl]phenyl dimethylcarbamate,

bp2013_v2_13_medicinal_and_pharmaceutical_substances_16 rivastigmine_4_2014_76_cs.png

C. 3-acetylphenyl ethyl(methyl)carbamate,

bp2013_v2_13_medicinal_and_pharmaceutical_substances_16 rivastigmine_5_2014_76_cs.png

D. 3-[(1R)-1-(dimethylamino)ethyl]phenyl ethyl(methyl)carbamate ((R)-enantiomer).

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板凳

楼主| l18089640 发表于 2015-12-18 10:18:02 | 只看该作者

工作QQ1 发表于 2015-12-17 06:31 PM
9 l' Z( k# @8 H; H8 e, r" {Rivastigmine
9 f$ a# N* ?( REuropean Union chaplet of stars0 C1 c2 c' {# ?. p
General Notices

谢谢,有德国的不