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Category Antibacterial (third-generation cephalosporin).

Cefotaxime Sodium contains not less than 96.0 per cent and not more than 101.0 per cent of C₁₆H₁₆N₅O₇S₂.Na, calculated on the dried basis.

Description White or slightly yellow powder. It is hygroscopic.

Solubility Freely soluble in water; sparingly soluble in methanol; practically insoluble in ether.

Contra-indication It is contra-indicated in patients who have shown hypersensitivity to any member of the cephalosporins.

Warning
          1. It should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins and should be administered with caution in patients who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction to penicillins or other drugs.
          2. It should be used with caution in patients with a history of gastro-intestinal diseases, particularly colitis.
          3. It should be administered with caution and in reduced dosage in the presence of markedly impaired renal function.
          4. It may cause local reaction at the injection site, gastro-intestinal disturbances, headache, hypersensitivity reactions, pseudomembranous colitis, and hematological abnormalities.
          5. Its overdosage can cause CNS irritation leading to seizures.
          6. Prolonged use may result in the overgrowth of nonsusceptible organisms, especially Pseudomonas and Candida.
          7. Risk-benefit should be considered if it is to be used in pregnant or nursing women.

Precaution Cefotaxime therapy should be discontinued if resistant strains of some organisms, especially Enterobacter, Pseudomonas aeruginosa, and Serratia have developed during therapy.

Additional information
          1. Group A beta-hemolytic streptococcal infections should be treated for at least 10 days to prevent the development of acute rheumatic fever or acute glomerulonephritis.
          2. Continue administration for a minimum of 48 to 72 hours after fever abates or after evidence of bacterial eradication has been obtained.

Packaging and storage Cefotaxime Sodium shall be kept in tightly closed containers, protected from light.

Labelling The label on the container states (1) storage condition; (2) parenteral grade.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Cefotaxime Sodium RS (Appendix 2.1) or with the reference spectrum of Cefotaxime Sodium.
          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 1, as obtained in the Assay.
          C. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel HF254 as the coating substance and a mixture of 15 volumes of acetone and 85 volumes of a 15.4 per cent w/v solution of ammonium acetate, previously adjusted to pH 6.2 with glacial acetic acid as the mobile phase. Apply separately to the plate, 1 μl of each of the following solutions. For solution (A) dissolve 20 mg of the test substance in 5.0 ml of a mixture of equal volumes of methanol and 0.067 M mixed phosphate buffer pH 7.0. For solution (B) dissolve 20 mg of Cefotaxime Sodium RS in 5.0 ml of a mixture of equal volumes of methanol and 0.067 M mixed phosphate buffer pH 7.0. For solution (C) dissolve 20 mg of Cefotaxime Sodium RS and 20 mg of Cefoxitin Sodium RS in 5.0 ml of a mixture of equal volumes of methanol and 0.067 M mixed phosphate buffer pH 7.0. After removal of the plate, allow it to dry and examine under ultraviolet light (254 nm). The principal spot in the chromatogram obtained from solution (A) is similar in position and size to that obtained from solution (B). The test is not valid unless the chromatogram obtained from solution (C) shows two clearly separated spots.
          D. It yields the reactions characteristic of sodium salts (Appendix 5.1).

Clarity and colour of solution Transfer 2.5 g of the test substance to a 25-ml volumetric flask. Dissolve in and dilute with carbon dioxide-free water to volume, mix, and examine immediately: the solution is clear. Measure the absorbance of this solution at 430 nm in a 1-cm cell, using carbon dioxide-free water as the blank: its absorbance is not more than 0.20. Transfer 10 ml of the solution to a glass test-tube, add 1 ml of glacial acetic acid, mix, and examine immediately: the solution is clear.

pH 4.5 to 6.5, in a 10.0 per cent w/v solution (Appendix 4.11).

Specific rotation +58º to +64º, calculated on the dried basis, determined in a 1.0 per cent w/v solution (Appendix 4.8).

Loss on drying Not more than 3.0 per cent w/w after drying at 105º for 3 hours (Appendix 4.15).

Absorbance Dissolve 20.0 mg in water and dilute to 100.0 ml with the same solvent. Dilute 10.0 ml of the solution to 100.0 ml with water. The specific absorbance at the maximum at 235 nm is between 360 to 390, calculated on the dried basis (Appendix 2.2). 

Related substances Carry out the test as described under Assay, using Assay preparation and Standard preparation 2. Continue the chromatography for at least eight times the retention time of the peak.
          In the chromatogram obtained from the Assay preparation, determine the percentage content of related substances by using the area of the principal peak in the chromatogram obtained from the Standard preparation 2 (1.0 per cent) as a comparison area.

Limits
          Any impurity Not more than the comparison
area (1.0 per cent).
          Total Not more than 3 times the comparison area
(3.0 per cent).

N,N-Dimethylaniline Not more than 20 ppm (Appendix 5.16.).

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
          Mobile phase Dissolve 3.5 g of potassium dihydrogenphosphate and 11.6 g of disodium hydrogenphosphate in 1000 ml of water at pH 7.0 and add 180 ml of methanol. Make adjustments if necessary.
          Standard preparation 1 Dissolve 25 mg of Cefotaxime Sodium RS in Mobile phase and dilute to 25.0 ml with the same solvent.
          Standard preparation 2 Dilute 1.0 ml of Standard preparation 1 to 100.0 ml with Mobile phase.
          Assay preparation Dissolve about 25 mg of Cefotaxime Sodium, accurately weighed, in Mobile phase and dilute to 25.0 ml with the same solvent.
          Resolution solution Add 1.0 ml of dilute hydrochloric acid to 4.0 ml of Assay preparation. Heat the solution at 40º for 2 hours. Add 5.0 ml of phosphate buffer solution pH 6.6 and 1.0 ml of sodium hydroxide TS.
          Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilane chemically bonded to porous silica or ceramic microparticles (5 μm), (b) Mobile phase at a flow rate of about 1 ml per minute, and (c) an ultraviolet photometer set at 235 nm. 
          To determine the suitability of the chromatographic system, chromatograph Resolution solution, and record the peak responses as directed under Procedure: the resolution factor between two principal peaks is not less than 3.5 and the symmetry factor of cefotaxime peak is less than 2.0. Chromatograph Standard preparation 1, and record the peak responses as directed under Procedure: the relative standard deviation for six replicate injections is not more than 1.0 per cent.
          Procedure Separately inject equal volumes (about 10 μl) of Standard preparation 1 and Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks.
          Calculation Calculate the content of C₁₆H₁₆N₅O₇S₂.Na in the Cefotaxime Sodium taken, using the declared content of C₁₆H₁₆N₅O₇S₂.Na in Cefotaxime Sodium RS.       

Other requirements Cefotaxime Sodium intended for parenteral administration complies with the following additional requirements.
          Bacterial endotoxins When tested as described in the “Test for Bacterial Endotoxins” (Appendix 8.5), it contains not more than 0.20 Endotoxin Unit per mg of cefotaxime.
          Sterility Complies with the “Sterility Test” (Method I, Appendix 10.1).