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Category Antiprotozoal; antibacterial.

      Metronidazole contains not less than 99.0 per cent and not more than 101.0 per cent of C₆H₉N₃O₃, calculated on the dried basis.

Description White or pale yellow crystalline powder; odourless.

Solubilily Sparingly soluble in water and in ethanol; slightly soluble in chloroform, and in ether.

Stability It darkens on exposure to light.

Contra-indication It is contra-indicated in patients with evidence or a history of blood dyscrasias and with active organic disease of CNS.

Warning

      1. It may cause nausea, dizziness, headache, anorexia, dry mouth, a sharp or unpleasant metallic taste, and stomach pain or cramps.

      2. It may enhance the activity of warfarin and other anticoagulants.

      3. Ingestion of alcohol may precipitate a disulfiramlike reaction.

      4. High doses or prolonged use may cause peripheral neuropathy (numbness, tingling, pain, or weakness in hands or feet).

      5. Risk-benefit should be considered if it is to be used in pregnant or nursing women.

Precaution

      1. Mild leukopenia has been reported. Total and differential leukocyte counts should therefore be made before and after treatment, especially if a second course of therapy is necessary.

      2. If abnormal neurological signs appear, treatment with metronidazole should be discontinued promptly.

Additional information

      1. To prevent reinfection in trichomoniasis, the sexual partner should receive concurrent therapy.

      2. It may cause dark urine without medical significance.

Packaging and storage Metronidazole shall be kept in well-closed containers, protected from light.

Identification

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

      B. The ultraviolet absorption spectrum of a 0.001 per cent w/v solution in 0.1 M hydrochloric acid, when observed between 230 and 350 nm, exhibits a maximum only at 277 nm; the absorbance of a 1-cm layer at this wavelength is about 0.38 (Appendix 2.2).

      C. Dissolve 100 mg in 4 ml of 0.5 M sulfuric acid, add 10 ml of trinitrophenol TS, and allow to stand: the precipitate, after washing with water  and drying at 105º, melts at about 150º (Appendix 4.3).

      D. Heat 10 mg in a water-bath for 5 minutes with 10 mg of zinc powder, 1 ml of water, and 5 drops of hydrochloric acid, cool in ice, add 0.5 ml of sodium nitrite TS, and remove the excess of nitrite with sulfamic acid. Add 0.5 ml of the product to a mixture of 0.5 ml of 2- naphthol TS  and 2 ml of 5 M sodium hydroxide: an orange-red colour is produced.

Melting range 159º to 163º (Appendix 4.3).

Loss on drying Not more than 0.5 per cent w/w after drying at 105º for 2 hours (Appendix 4.15).

Heavy metals Not more than 20 ppm (Method III, Appendix 5.2). Use 1 g; for the Standard Preparation, use 2 ml of lead standard solution (10 ppm Pb).

Sulfated ash Not more than 0.1 per cent w/w (Appendix 5.3).

Related substances 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 9 volumes of chloroform  and 1 volume of diethylamine as  the mobile phase.

      Test solution A Dissolve an accurately weighed quantity of the test substance in acetone  to obtain a solution containing 20 mg per ml.

      Test solution B Dilute Test solution  A quantitatively with acetone  to obtain a solution containing 100 μg per ml.

      Procedure Apply separately to the plate, 5 μl of each of the solutions. After removal of the plate, allow it to dry in air and examine under ultraviolet light (254 nm). Any spot obtained from Test solution A, other than the principal spot, is not more intense than that obtained from Test solution B.

Non-basic substances Dissolve 1 g of the test substance in 10 ml of diluted hydrochloric acid (1 in 2). The solution is clear.

Assay Dissolve about 450 mg of Metronidazole, accurately weighed, in 10 ml of anhydrous glacial acetic acid, warming slightly and cooling if necessary to effect solution. Titrate with 0.1 M perchloric acid VS, using 1-naphtholbenzein TS as indicator or determining the end-point potentiometrically (Appendix 6.1). Perform a blank determination, and make any necessary correction. Each ml of 0.1 M perchloric acid  is equivalent to 17.12 mg of C₆H₉N₃O₃.