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CEFADROXIL

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Category Antibacterial (first-generation cephalosporin).

          Cefadroxil contains not less than 95.0 per cent and not more than 102.0 per cent of C16H17N3O5S, calculated on the anhydrous basis.

Description White or almost white powder.

Solubility Slightly soluble in water; very slightly soluble in ethanol.

Contra-indication; Warning; Precaution See under Cephalexin, p. 58.

Additional information Cefadroxil is used as an alternative to amoxicillin or ampicillin for prophylaxis against alpha-hemolytic (viridans group) streptococcal endocarditis in penicillin-allergic individuals considered to be at risk for bacterial endocarditis following certain dental or upper respiratory tract procedures.

Packaging and storage Cefadroxil 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 (1) storagevcondition; (2) whether it is in the monohydrate orvhemihydrate form.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Cefadroxil RS (Appendix 2.1) or with the reference spectrum of Cefadroxil.
          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.
          C. Place 2 mg in a test-tube. Moisten with one drop of water, add 2 ml of sulfuric-formaldehyde TS and mix: the solution is yellow. Place the test-tube in a waterbath for 1 minute: an orange colour develops.

pH 4.0 to 6.0, in a 5.0 per cent w/v suspension (Appendix 4.11).

Specific rotation +165º to +178º, calculated on the anhydrous basis, determined in a 1.0 per cent w/v solution (Appendix 4.8).

Water Not less than 4.2 per cent w/w and not more than 6.0 per cent w/w except that where it is labelled as being in the hemihydrate form it is not less than 2.4 per cent w/w and not more than 4.5 per cent w/w (Karl Fischer Method, Appendix 4.12).

Absorbance Dissolve 20.0 mg in phosphate buffer solution pH 6.0 and dilute to 100.0 ml with the same solvent. The absorbance of the solution measured at 330 nm is not greater than 0.05. Dilute 10.0 ml of the solution to 100.0 ml with phosphate buffer solution pH 6.0. The light absorption spectrum of the diluted solution, when observed between 235 nm and 340 nm, exhibits a maximum at about 264 nm; the specific absorbance at this maximum is between 225 and 250, calculated on the anhydrous basis (Appendix 2.2).

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

Related substances Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
     Mobile phase
          Mobile phase A Dissolve 2.72 g of potassium dihydrogenphosphate in 800 ml of water, adjust the pH to 5.0 with 1 M potassium hydroxide and dilute to 1000 ml with water.
          Mobile phase B Use methanol.
     Phosphate buffer solution pH 7.0 Dissolve 28.4 g of anhydrous disodium hydrogenphosphate in 800 ml of water. Adjust the pH using a 30 per cent w/w solution of phosphoric acid and dilute to 1000 ml with water.
     Standard solution (a) Dissolve 10.0 mg of D-α- (4-Hydroxyphenyl) glycine RS (impurity A) in Mobile phase A and dilute to 10.0 ml with Mobile phase A.
     Standard solution (b) Dissolve 10.0 mg of 7- Aminodes-acetoxycephalosporanic Acid RS (impurity B) in Phosphate buffer solution pH 7.0, and dilute to 10.0 ml with the same buffer solution.
     Standard solution (c) Dilute 1.0 ml of Standard solution (a) and 1.0 ml of Standard solution (b) to 100.0 ml with Mobile phase A.
     Standard solution (d) Dissolve 10.0 mg of dimethylformamide and 10.0 mg of dimethylacetamide in Mobile phase A and dilute to 10.0 ml with Mobile phase A. Dilute 1.0 ml to 100.0 ml with Mobile phase A.
     Standard solution (e) Dilute 1.0 ml of Standard solution (c) to 25.0 ml with Mobile phase A. Test solution Dissolve 50.0 mg of the test substance in Mobile phase A and dilute to 50.0 ml with Mobile phase A.
     Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilane chemically bonded to porous silica or ceramic microparticles (5 μm), (b) Mobile phases at a flow rate of about 1.5 ml per minute, and (c) an ultraviolet photometer set at 220 nm. The step gradient of mobile phases is as follows:


 

          To determine the suitability of the chromatographic system, separately chromatograph Standard solutions (c) and (e), and record the peak responses as directed under 
Procedure: the resolution factor between the peaks due to impurity A and to impurity B is not less than 5.0 in the chromatogram obtained from Standard solution (c) and the signal-to-noise ratio is not less than 10 for the second peak in the chromatogram obtained from Standard solution (e).

          In the chromatogram obtained from Test solution, determine the percentage content of related substances by using the areas of the first peak (impurity A) and the second peak (impurity B) in the chromatogram obtained from Standard solution (c) as a comparison area (1.0 per cent).

     Limits
          Disregard limit Disregard the peaks due to dimethylformamide and dimethylacetamide; not more than 0.05 times the area of the second peak in the chromatogram obtained from Standard solution (c) (0.05 per cent).
          Impurity A Not more than the area of the first peak in the chromatogram obtained from Standard solution (c) (1.0 per cent).
          Any other impurity Not more than the area of the second peak in the chromatogram obtained from Standard solution (c) (1.0 per cent).
          Total Not more than 3 times the area of the second peak in the chromatogram obtained from Standard solution (c) (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 4 volumes of acetonitrile and 96 volumes of a 0.272 per cent w/v solution of potassium dihydrogenphosphate. Make adjustments if necessary.
          Resolution solution Dissolve about 5 mg of Cefadroxil RS and about 50 mg of Amoxicillin Trihydrate RS in Mobile phase and dilute to 100.0 ml with the same solvent.                 

          Standard preparation Dissolve about 50 mg of Cefadroxil RS, accurately weighed, in Mobile phase and dilute to 100.0 ml with the same solvent.
          Assay preparation Dissolve about 50 mg of Cefadroxil, accurately weighed, in Mobile phase and dilute to 100.0 ml with the same 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 (5 μm), (b) Mobile phase at a flow rate of about 1.0 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 cefadroxil and amoxicillin peaks is not less than 5.0. 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 and the symmetry factor for the cefadroxil peak is not more than 2.2.
          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 C16H17N3O5S in the Cefadroxil taken, using the declared content of C16H17N3O5S in Cefadroxil RS.

MONOGRAPHS • CEFADROXIL
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หมายเหตุ / Note : TP II 2011 PAGE 36 - 38