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Category Antibacterial (third-generation cephalosporin).

Ceftriaxone Sodium contains not less than 96.0 per cent and not more than 102.0 per cent of C₁₈H₁₆N₈O₇S₃.2Na, calculated on the anhydrous basis.

Description Almost white or yellowish, crystalline powder; hygroscopic.

Solubility Freely soluble in water; sparingly soluble in methanol; very slightly soluble in ethanol.

Stability It is slightly hygroscopic.

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 and in hyperbilirubinemic neonates, especially premature neonates.
          3. It should be administered with caution and in reduced dosage in patients with markedly impaired renal function or in those with impaired hepatic and renal functions.
          4. It may cause gastro-intestinal disturbances, hypersensitivity reactions, pseudomembranous colitis, pseudolithiasis (or biliary “sludge”), and hematological abnormalities.
          5. Prolonged use may result in the overgrowth of nonsusceptible organisms, especially Enterobacter, Pseudomonas, Enterococci, or Candida.
          6. Risk-benefit should be considered if it is to be used in pregnant or nursing women.

Precaution 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.

Additional information The admixture of beta-lactam antibacterials (penicillins and cephalosporins) and aminoglycosides may result in substantial mutual inactivation. If they are administered concurrently, they should be administered in separate sites and do not mix them in the same intravenous bag or bottle.

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

Labelling The label on the container states parenteral grade.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Ceftriaxone Sodium RS (Appendix 2.1) or with the reference spectrum of Ceftriaxone Sodium.
          B. The retention time of the major peak in the chromatogram of the Assay preparation 1 corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
          C. It yields the reactions characteristic of sodium salts (Appendix 5.1).

Clarity of solution A solution containing the equivalent of 12.0 per cent w/v of ceftriaxone in carbon dioxide-free water is clear (Appendix 4.1).

Crystallinity It is crystalline (Appendix 4.14).

pH 6.0 to 8.0, in a 1.20 per cent w/v solution (Appendix 4.11).

Specific rotation –155º to –170º, calculated on the anhydrous basis, determined in a 1.0 per cent w/v solution (Appendix 4.8).

Related substances Carry out the test as described under Assay using Assay preparation 1, Resolution solution and Assay preparation 2. Allow the chromatography to proceed for at least twice the retention time of the principal peak.
          In the chromatogram obtained from the Assay preparation 1, determine the percentage content of related substances by using the area of the principal peak in the chromatogram obtained from the Assay preparation 2 (1.0 per cent) as a comparison area.

Limits
          Disregard limit Not more than 0.1 times the comparison area (0.1 per cent).
          Any impurity Not more than the comparison area (1.0 per cent).
          Total Not more than 4 times the comparison area (4.0 per cent).

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

Water 8.0 to 11.0 per cent w/w (Karl Fischer Method, Appendix 4.12). Use 100 mg.

Assay Carry out the determination as described in the
“High-pressure Liquid Chromatography” (Appendix
3.5).
          Mobile phase Dissolve 2.0 g of tetradecylammonium bromide and 2.0 g of tetraheptylammonium bromide in a mixture of 440 ml of water, 55 ml of 0.067 M phosphate buffer solution pH 7.0, 5 ml of citrate buffer solution pH 5.0 prepared by dissolving 20.17 g of citric acid in 800 ml of water, adjusting to pH 5.0 with 10 M sodium hydroxide and diluting to 1000.0 ml with water, and 500 ml of acetronitrile. Make adjustments if necessary.
          Standard preparation Dissolve 30.0 mg of Ceftriaxone Sodium RS, in Mobile phase and dilute to 100.0 ml with the same solvent.
          Assay preparation 1 Dissolve 30 mg of Ceftriaxone Sodium, accurately weighed, in Mobile phase and dilute to 100.0 ml with the same solvent.
          Assay preparation 2 Dilute 1.0 ml of Assay preparation 1 to 100.0 ml with the Mobile phase.
          Resolution solution Dissolve an accurately weighed quantity of each of Ceftriaxone Sodium RS and Ceftriaxone Sodium E-isomer RS in Mobile phase to obtain a solution having each known concentration of 50 μg per ml.
          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 microparticles (5 μm), (b) Mobile phase at a flow rate of about 1.5 ml per minute, and (c) an ultraviolet photometer set at 254 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 the two principal peaks is not less than 3.0. Chromatograph Standard preparation, and record the peak responses as directed under Procedure: the relative standard deviation for 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 C₁₈H₁₆N₈O₇S₃.2Na in the Ceftriaxone Sodium taken, using the declared content of C₁₈H₁₆N₈O₇S₃.2Na.3½H2O in Ceftriaxone Sodium RS. Each mg of C₁₈H₁₆N₈O₇S₃.2Na.3½H₂O is equivalent to 0.9047 mg of C₁₈H₁₆N₈O₇S₃.2Na.

Other requirements Ceftriaxone 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 ceftriaxone.
          Sterility Complies with the “Sterility Test” (Method I, Appendix 10.1).