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CLOXACILLIN SODIUM

Category Antibacterial.

Cloxacillin Sodium contains not less than 90.0 per cent and not more than 96.0 per cent of C19H18ClN3O5S, calculated on the anhydrous basis.

Description White, crystalline powder.

Solubility Freely soluble in water and in methanol; soluble in ethanol; slightly soluble in acetone and in chloroform.

Stability It is hygroscopic. Even in the absence of light, Cloxacillin Sodium is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures.

Contra-indication; Warning; Precaution See under Penicillin V Potassium, p. 140.

Additional information It is a preferred drug for the treatment of mild to moderate Staphylococcal infections of the skin and soft tissue, respiratory and genitourinary tracts, and joints.
          See also under Penicillin V Potassium, p. 140.

Packaging and storage Cloxacillin Sodium shall be kept in tightly closed containers and stored at a temperature temperature not exceeding 25º. If it is intended for parenteral administration, it shall also be kept under sterile condition.
          Labelling The label on the container states (1) storage condition; (2) parenteral or non-parenteral grade.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Cloxacillin Sodium RS (Appendix 2.1) or with the reference spectrum of Cloxacillin Sodium. It yields the reactions characteristic of penicillins (Appendix 5.1).
          B. Ignite 20 mg and dissolve the residue in dilute acetic acid. The solution yields the reactions characteristic of sodium salts (Appendix 5.1).
          D. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silanized silica gel H as the coating substance and a mixture of 30 volumes of acetone and 70 volumes of a 15.4 per cent w/v of solution of ammonium acetate, adjusted to pH 5.0 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 25 mg of Cloxacillin Sodium in 5 ml of water. Solution (B) contains 5 mg per ml of Cloxacillin Sodium RS and solution (C) contains 5 mg per ml of each of Cloxacillin Sodium RS, Dicloxacillin Sodium RS and Flucloxacillin Sodium RS. After removal of the plate, allow it to dry in air, expose it to iodine vapour until the spots appear. The principal spot in the chromatogram obtained from solution (A) corresponds to that in the chromatogram obtained from solution (B). The test is not valid unless the chromatogram obtained from solution (C) shows three clearly separated spots.

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

pH 4.5 to 7.5, in a 1.0 per cent w/v solution (Appendix 4.11).

Specific rotation +160º to +169º, calculated on the anhydrous basis, determined in a 1.0 per cent w/v solution (Appendix 4.8).

Water Not less than 3.0 per cent w/w and not more than 5.0 per cent w/w (Karl Fischer Method, Appendix 4.12).

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

2-Ethylhexanoic acid Not more than 0.8 per cent w/w. If manufactured by a process that may leave residues of 2-ethylhexanoic acid in the product. Carry out the determination as described in the “Gas Chromatography” (Appendix 3.4), using a suitable validated method.

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
          Mobile phase Prepare a mixture of 25 volumes of acetonitrile and 75 volumes of a 0.27 per cent w/v solution of potassium dihydrogenphosphate adjusted to pH 5.0 with 2 M sodium hydroxide. Make adjustments if necessary.
          Resolution solution Dissolve an accurately weighed quantity of each of Cloxacillin Sodium RS and Flucloxacillin Sodium RS in Mobile phase and dilute quantitatively to obtain a solution having known concentrations of about 100 μg per ml.
          Standard preparation Dissolve an accurately weighed quantity of Cloxacillin Sodium RS in Mobile phase to obtain a solution having a known concentration of about 1 mg per ml. Dilute 5.0 ml of the solution to 50.0 ml with Mobile phase.
          Assay preparation A Dissolve about 50 mg of Cloxacillin Sodium in Mobile phase and dilute to 50.0 ml with Mobile phase.
          Assay preparation B Dilute 5.0 ml of Assay preparation A to 50.0 ml with Mobile phase.
          Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4 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 225 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 cloxacillin (the first peak) and flucloxacillin (the second peak) is not less than 2.5. Chromatograph Standard preparation, 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 20 μl) of Standard preparation and Assay preparation B into the chromatograph, record the chromatograms, and measure the responses for the major peaks.
          Calculation Calculate the content of C19H18ClN3O5S in the Cloxacillin Sodium taken, using the declared content of C19H18ClN3O5S in Cloxacillin Sodium RS.

Other requirements Cloxacillin Sodium intended for parenteral administration complies with the following additional requirements.
          Bacterial endotoxins When test as described in the “Test for Bacterial Endotoxins” (Appendix 8.5), itcontainsitcontains not more than 0.40 Endotoxin Unit per mg of cloxacillin.
         Sterility Complies with the “Sterility Test” (Method I, Appendix 10.1).

MONOGRAPHS • CLOXACILLIN SODIUM
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หมายเหตุ / Note : TP II 2011 PAGE 87 - 88