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CEFUROXIME AXETIL

 

Category Antibacterial (second-generation cephalosporin).

Cefuroxime Axetil contains the equivalent of not less than 96.0 per cent and not more than 102.0 per cent of a mixture of the two diastereoisomers of C20H22N4O10S, calculated on the anhydrous and acetone- free basis.

Description White or almost white powder.

Solubility Slightly soluble in water and in ethanol; soluble in acetone, ethyl acetate and in methanol.

Contra-indication; Additional information See under Cephalexin, p. 58.

Warning It may cause transient increase in serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) and alkaline phosphatase concentrations and jaundice.
          See also under Cephalexin, p. 58.

Packaging and storage Cefuroxime Axetil shall be kept in tightly closed containers, protected from light and stored at a temperature not exceeding 25º.

Labelling The label on the container states whether it is amorphous or crystalline.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Cefuroxime Axetil RS (Appendix 2.1) or with the reference spectrum of Cefuroxime Axetil.
          B. The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.

Diastereoisomer ratio Carry out the test as described under Assay.
          In the chromatogram obtained from Assay preparation 1, the ratio of the peak due to cefuroxime axetil diastereoisomer A to the sum of the peaks due to cefuroxime axetil diastereoisomers A and B is between 0.48 and 0.55 by normalization.

Acetone Not more than 1.1 per cent. Carry out the test as described in the “Gas Chromatography” (Appendix 3.4).
          Standard preparation Transfer 5.0 ml of acetone to a 1000-ml volumetric flask, dilute with water to volume, and mix (Solution A). Transfer 50.0 ml of Solution A to a 500-ml volumetric flask, dilute with water to volume, and mix to obtain a solution having concentration of acetone of 0.050 per cent v/v.
          Test preparation Transfer 5.0 g of Cefuroxime Axetil to a 50-ml volumetric flask, dissolve in and dilute with water to volume, and mix. Transfer 3.0 ml of the resulting solution to a 15-ml centrifuge tube, cool in an ice-water-bath for 2 minutes, and add 3.0 ml of 0.24 M hydrochloric acid while swirling vigorously. Centrifuge to obtain a clear solution.
          Chromatographic system The chromatographic procedure may be carried out using (a) a glass column (1.8 m × 6.3 mm) containing styrene-divinylbenzene copolymer packed with 60- to 80-mesh silane-treated glass beads with a nominal surface area of less than 50 m2 per g and an average pore diameter of 0.3 to 0.4 μm and maintained at 110º, (b) the injection port and the detector block are maintained at 100º and 200º, respectively, (c) nitrogen as the carrier gas at a flow rate of about 50 ml per minute, and (d) a flame ionization detector.
          Chromatograph Standard preparation, and record the peak responses as directed under Procedure.
          Procedure Separately inject equal volumes of about 2 μl of Standard preparation and Test preparation into the chromatograph, record the chromatograms, and measure the area for the acetone peak. The test is not valid unless the acetone peak is not less than 160 theoretical plates, the symmetry factor for the acetone peak is not more than 1.3, and the relative standard deviation for replicate injections is not more than 5 per cent.
          Calculation Calculate the percentages of acetone
from the expression:

15.8P(ru/rs),

in which P is the percentage (v/v) of acetone in Standard preparation, and ru and rs are the acetone peak responses of Test preparation and Standard preparation, respectively.

Water Not more than 1.5 per cent w/w (Karl Fischer Method, Appendix 4.12). Use 400 mg.

Related substances Carry out the test as described under Assay using Standard preparation, Assay preparation 1, Assay preparation 2, Assay preparation 3, and Assay preparation 4. Prepare the solutions immediately before use.
     In the chromatogram obtained from the Assay preparation 1, determine the percentage content of related substances by using the sum of areas of the two principal peaks (Cefuroxime axetil diastereoisomer B and Cefuroxime axetil diastereoisomer A), in the chromatogram obtained from the Assay preparation 2 (1.0 per cent) as a comparison area.
     Limits
          Disregard
limit Not more than 0.05 times the comparison area (0.05 per cent).
          E-isomers The areas of the pair of peaks corresponding to the E-isomers in the Assay preparation 4 is not more than the comparison area (1.0 per cent).
          Δ3-isomers The areas of the pair of peaks corresponding to the Δ3-isomers in the Assay preparation 3 is not more than 1.5 times the comparison area (1.5 per cent).

          Any impurity Not more than 0.5 times the comparison area (0.5 per cent).
          Total Not more than 3 times the comparison area (3.0 per cent).

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
          Mobile phase Prepare a mixture of 38 volumes of methanol and 62 volumes of a 2.3 per cent w/v solution of ammonium dihydrogenphosphate. Make adjustments if necessary.
          Standard preparation Dissolve about 10 mg of Cefuroxime Axetil RS, accurately weighed, in Mobile phase and dilute to 50.0 ml with Mobile phase. Prepare the solution immediately before use.
          Assay preparation 1 Dissolve about 10 mg of Cefuroxime Axetil, accurately weighed, in Mobile phase and dilute to 50.0 ml with Mobile phase. Prepare the solution immediately before use.
          Assay preparation 2 Dilute 1.0 ml of Assay preparation 1 to 100.0 ml with Mobile phase.
          Assay preparation 3 Heat 5 ml of Assay preparation 1 at 60º for 1 hour to generate Δ3-isomers.
          Assay preparation 4 Expose 5 ml of Assay preparation 1 to ultraviolet light at 254 nm for 24 hours to generate E-isomers.
          Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with trimethylsilyl group chemically bonded to porous silica microparticles (5 μm), (b) Mobile phase at a flow rate of about 1.0 ml per minute, and (c) an ultraviolet photometer set at 278 nm.
          To determine the suitability of the chromatographic system, chromatograph Assay preparations 2, 3, 4 and Standard preparation, and record the peak responses as directed under Procedure: the relative retention times are about 0.9 for cefuroxime axetil diastereoisomer B, 1.2 for cefuroxime axetil-Δ3-isomers, 1.7 and 2.1 for Eisomer and 1.0 for Cefuroxime axetil diastereoisomer A. Chromatograph Assay preparation 2 and record the peak responses as directed under Procedure: the resolution factor between cefuroxime axetil diastereoisomer A and cefuroxime axetil-Δ3-isomer peaks is not less than 1.5. Chromatograph Standard preparation, and record the peak responses as directed under Procedure: the resolution factor between cefuroxime axetil diastereoisomer A and B peaks is not less than 1.5 and the relative standard deviation for six replicate injections is not more than 2.0 per cent.
          Procedure Separately inject equal volumes (about 20 μl) of Standard preparation and Assay preparation 1 into the chromatograph, record the chromatograms, and measure the responses for the major peaks.
          Calculation Calculate the content of C20H22N4O10S in the Cefuroxime Axetil taken from the sum of areas of the two diastereoisomer peaks, using the declared content of C20H22N4O10S in Cefuroxime Axetil RS.

          

MONOGRAPHS • CEFUROXIME AXETIL
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หมายเหตุ / Note : TP II 2011 PAGE 52 - 54