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Category Antibacterial (second-generation cephalosporin).

          Cefaclor contains not less than 95.0 per cent and not more than 102.0 per cent of C₁₅H₁₄ClN₃O₄S, calculated on the anhydrous basis.

Description White to off-white crystalline powder.

Solubility Slightly soluble in water; practically insoluble in methanol and in dichloromethane.

Stability In aqueous solutions, it rapidly loses activity.

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

Warning Serum sickness-like reactions consisting of erythema multiforme or maculopapular pruritic rash or urticaria have been reported most frequently in pediatric patients younger than 6 years of age.
          See also under Cephalexin, p. 58.

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.
          See also under Cephalexin, p. 58.

Packaging and storage Cefaclor shall be kept in tightly closed containers.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Cefaclor RS (Appendix 2.1) or with the reference spectrum of Cefaclor.
          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.

Crystallinity It is crystalline (Method I, Appendix 4.14).

pH 3.0 to 4.5, in a 2.5 per cent w/v suspension (Appendix 4.11).

Water Not less than 3.0 per cent w/w and not more than 6.5 per cent w/w (Karl Fischer Method, Appendix 4.12). Use 200 mg.

Chromatographic purity Not more than 0.5 per cent of any individual cefaclor-related substance is found, and the sum of all cefaclor-related substances found is not more than 2.0 per cent. In an acceptable determination, the difference between duplicate determinations of total cefaclor-related compounds is not more than 0.2 per cent absolute, or the variation from the mean of the two values is not more than 10 per cent, whichever is greater. Carry out the test as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).

          Solvent Dissolve 2.7 g of sodium dihydrogenphosphate in 1000 ml of water, and adjust with phosphoric acid to a pH of 2.5.
          Solution A Dissolve 7.8 g of sodium dihydrogenphosphate in 1000 ml of water, and adjust with phosphoric acid to a pH of 4.0. Make adjustments if necessary.
          Solution B Prepare a mixture of 11 volumes of Solution A and 9 volume of acetonitrile, degassing for not more than 2 minutes. Make adjustments if necessary. Reducing the acetonitrile content increases the retention time of cefaclor and increases the resolution between the delta-3-cefaclor and cefaclor.
          Mobile phase Use variable mixtures of Solution A and Solution B as directed for Chromatographic system.
          Standard solutions Dissolve an accurately weighed quantity of Cefaclor RS in Solvent to obtain a solution having a known concentration of about 50 μg per ml. Sonicate briefly, if necessary, to achieve dissolution, and avoid heating (Standard solution 1). Dilute accurately 2 volumes of Standard solution 1 with 1 volume of Solvent to obtain a solution having a known concentration of about 33 μg per ml (Standard solution 2). Dilute accurately 1 volume of Standard solution 1 with 3 volumes of Solvent to obtain a solution having a known concentration of about 12.5 μg per ml (Standard solution 3). Use these Standard solutions on the day prepared.
          Resolution solution Dissolve a quantity of Delta-3- cefaclor RS in Standard solution 2 to obtain a solution containing 50 μg per ml.
          Test solutions Transfer about 50 mg of the test substance, accurately weighed, to each of two 10-ml volumetric flasks, dilute with Solvent to volume, and mix. Sonicate briefly, if necessary, to achieve dissolution, and avoid heating. (Note Use these Test solutions within 2 hours when stored at room temperature or within 20 hours when stored under refrigeration.)
          Blank Use the Solvent.
          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
(3 to 10 μm), (b) Mobile phase at a flow rate of about 1 ml per minute, (c) an ultraviolet photometer set at 220 nm. The system is equilibrated with a mixture of 95 per cent Solution A and 5 per cent Solution B, and immediately following the injection of Standard solution, Resolution solution, Test solution, or Blank, the proportion of Solution B is increased linearly from 5 to 25 per cent over a period of 30 minutes. The proportion of Solution B is then increased linearly to 100 per cent over a period of 15 minutes, and held for 10 minutes. (Note After this the proportion of Solution B is returned to 5 per cent, and the system is allowed to equilibrate for 10 minutes at the initial composition before the next injection.) To determine the suitability of chromatographic system, chromatograph Resolution solution as directed under Procedure: the retention time for the cefaclor peak is between 23 and 29 minutes. Chromatograph Standard solution, and record the responses as directed under Procedure: the symmetry factor is not more than 1.5, and the resolution factor between the delta-3-cefaclor peak and the cefaclor peak is not less than 2.0. Chromatograph Blank as directed under Procedure. Examine the chromatogram for any extraneous peaks, and disregard any corresponding peaks observed in the chromatogram of Test solutions. (Note Take care to ensure that any extraneous peaks observed do not represent carryover from previous injections.) Chromatograph Standard solutions as directed under Procedure. Plot the responses for the cefaclor peaks in the three chromatograms versus their concentrations, in μg of cefaclor(C₁₅H₁₄ClN₃O₄S) per ml, and draw a straight line through the three points and zero (Standard response line). The relative standard deviation of replicate injections is not more than 3 per cent.
          Procedure (Note Use peak areas where peak responses are indicated.) Separately inject equal volumes (about 20 μl) of the two Test solutions into the chromatograph, record the chromatograms, and measure the responses for all of the peaks except that for cefaclor. From Standard response line, determine the concentration, in mg per ml, of cefaclor-related compound represented by each peak other than the cefaclor peak. Calculate the percentage of cefaclor-related compound represented by each such peak by the expression:

IP/W,

in which I is the concentration, in mg per ml, of cefaclorrelated substance in the respective Test solution as determined from Standard response line, P is the designated potency, in μg per mg, of Cefaclor RS, and W is the weight, in mg, of the portion of the test substance taken to prepare the respective Test solution. Determine the mean values for each cefaclor-related substance.

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
          Mobile phase Dissolve 1 g of sodium 1-pentanesulfonate in a mixture of 780 ml of water and 10 ml of triethylamine. Adjust with phosphoric acid to a pH of 2.5±0.1,add 220 ml of methanol, and mix. Make adjustments if
necessary.
          Resolution solution Prepare a solution in Mobile phase containing about 300 μg of cefaclor and 300 μg of Delta-3-cefaclor RS per ml.
          Standard preparation Transfer about 15 mg of Cefaclor RS, accurately weighed, to a 50-ml volumetric flask, dilute with Mobile phase to volume, and mix. Sonicate briefly, if necessary, to achieve dissolution, and avoid heating the solution. (Note Use this Standard preparation within 8 hours if stored at room temperature, or within 20 hours if stored under refrigeration.)
          Assay preparation Transfer about 15 mg of Cefaclor, accurately weighed, to a 50-ml volumetric flask, dilute with Mobile phase to volume, and mix. Sonicate briefly, if necessary, to achieve dissolution, and avoid heating the solution. (Note Use this Assay preparation within 8 hours if stored at room temperature, or within 20 hours if stored under refrigeration.)
          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 1.5 ml per minute, and (c) an ultraviolet photometer set at 265 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 cefaclor and delta-3-cefaclor peaks is not less than 2.5, the relative retention times are about 0.8 for cefaclor and 1.0 for delta-3-cefaclor, the relative standard deviation for replicate injections is not more than 2.0 per cent and the symmetry factor for the cefaclor peak is not more than 1.5.
          Procedure Separately inject equal volumes (about 20 μl) of Standard preparation and Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks.
          Calculation Calculate the content of C₁₅H₁₄ClN₃O₄S in the Cefaclor taken, using the declared content of C₁₅H₁₄ClN₃O₄S in Cefaclor RS.