美罗培南三水合物（meropenem trihydrate)BP2017标准

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meropenem trihydrate-BP2017
Updated Ph. Eur. 9.0, effective 01/01/2017
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Meropenem Trihydrate
General Notices

(Ph. Eur. monograph 2234)
C17H25N3O5S,3H2O  437.5 119478-56-7 
Action and use
Carbapenem antibacterial.

Ph Eur

DEFINITION
(4R,5S,6S)-3-[[(3S,5S)-5-[(Dimethylamino)carbonyl]pyrrolidin-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate.

Semi-synthetic product derived from a fermentation product, or synthetic product.

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

CHARACTERS
Appearance
White or light yellow, crystalline powder.

Solubility
Sparingly soluble in water, practically insoluble in ethanol (96 per cent) and in methylene chloride.

IDENTIFICATION
Infrared absorption spectrophotometry (2.2.24).

Comparisonmeropenem trihydrate CRS.

TESTS
Appearance of solution
The solution is clear (2.2.1) and not more intensely coloured than reference solution Y5 (2.2.2, Method II).

Dissolve 1.0 g in 20 mL of a 50 g/L solution of sodium hydrogen carbonate R.

pH (2.2.3)
4.0 to 6.0.

Dissolve 0.20 g in carbon dioxide-free water R and dilute to 20 mL with the same solvent.

Specific optical rotation (2.2.7)
-21 to -17 (anhydrous substance).

Dissolve 0.125 g in water R and dilute to 25.0 mL with the same solvent.

Related substances
Liquid chromatography (2.2.29). Prepare test solutions (a) and (b) and reference solution (c) immediately before use. Prepare and store reference solution (a) at 4 °C and use within 6 h.

Solvent mixture To 1.0 mL of triethylamine R add 900 mL of water for chromatography R. Adjust to pH 5.0 with dilute phosphoric acid R and dilute to 1000.0 mL with water for chromatography R.

Test solution (a) Dissolve 0.100 g of the substance to be examined in the solvent mixture and dilute to 25.0 mL with the solvent mixture.

Test solution (b) Dissolve 50.0 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 test solution (a) to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.

Reference solution (b) In order to prepare impurities A and B in-situ, heat 10 mL of test solution (a) to 60 °C for about 20 min or, alternatively, allow 10 mL of test solution (a) to stand at room temperature for about 8 h.

Reference solution (c) Dissolve 50.0 mg of meropenem trihydrate CRS in the mobile phase and dilute to 100.0 mL with the mobile phase.

Column:
— size: l = 0.25 m, Ø = 4.6 mm;
— stationary phase: base-deactivated end-capped octadecylsilyl silica gel for chromatography R (5 μm);
— temperature: 40 °C.
Mobile phaseacetonitrile R1, solvent mixture (7:100 V/V).

Flow rate 1.6 mL/min.

Detection Spectrophotometer at 220 nm.

Injection 10 μL of test solution (a) and reference solutions (a) and (b).

Run time 4 times the retention time of meropenem.

Relative retention With reference to meropenem (retention time = about 7 min): impurity A = about 0.5; impurity B = about 2.2.

System suitability: reference solution (b):
— resolution: minimum 5.0 between the peaks due to impurity A and meropenem.
Limits:
— correction factor: for the calculation of content, multiply the peak area of impurity A by 1.6;
— impurity A: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent);
— impurity B: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent);
— unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);
— sum of impurities other than A and B: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.3 per cent);
— disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).
For meropenem trihydrate produced by a fully synthetic process:
— unspecified impurities: for each impurity, not more than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent);
— disregard limit: 0.3 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.03 per cent).
Water (2.5.12)
11.4 per cent to 13.4 per cent, determined on 0.100 g.

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

Bacterial endotoxins (2.6.14)
Less than 0.125 IU/mg, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins.

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

Injection Test solution (b) and reference solution (c).

Calculate the percentage content of C17H25N3O5S taking into account the assigned content of meropenem trihydrate CRS.

STORAGE
If the substance is sterile, store in a sterile, airtight, tamper-proof container.

LABELLING
The label states, where applicable, that the substance is suitable for use in the manufacture of parenteral preparations.

IMPURITIES
Specified impurities A, B

A. (4R,5S)-5-[(1S,2R)-1-carboxy-2-hydroxypropyl]-3-[[(3S,5S)-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl]sulfanyl]-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid,
B. (4R,5S,6S)-3-[[(3S,5S)-1-[(2S,3R)-2-[(2S,3R)-5-carboxy-4-[[(3S,5S)-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl]sulfanyl]-3-methyl-2,3-dihydro-1H-pyrrol-2-yl]-3-hydroxybutanoyl]-5-[(dimethylamino)carbonyl]pyrrolidin-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Ph Eur

非常非常感谢！