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PYRAZINAMIDE

Category Antibacterial (antituberculosis).

      Pyrazinamide contains not less than 99.0 per cent and not more than 100.5 per cent of C5H5N3O, calculated on the anhydrous basis.

Description White or almost white, crystalline powder; odourless or almost odourless.

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

Contra-indication It is contra-indicated in patients with severe hepatic damage and acute gout. 

Warning

      1. It should be used with caution in patients with diabetes mellitus, impaired hepatic or renal function and a history of out.

      2. It may cause liver damage, anorexia, nausea, vomiting, arthralgia, fever, difficulty in micturition, anemia, porphyria, hyperuricemia, rashes and photosensitivity.

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

Precaution

      1. Frequent liver function tests and blood uric acid determinations should be performed during treatment.

      2. The drug should be discontinued and not to be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis become evident.

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

Identification

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

      B. The ultraviolet absorption spectrum of a 0.001 per cent w/v solution, when observed between 230 and 350 nm, exhibits a maximum at 268 nm and a small one at 310 nm; the absorbance of a 1-cm layer at 268 nm is about 0.66 (Appendix 2.2).

      C. Dissolve 100 mg in 10 ml of water and add 1 ml of a 1.5 per cent w/v solution of iron(II) sulfate: an orange-red colour develops turning to blue on the addition of 1 ml of 2 M sodium hydroxide.

D. Boil 20 mg with 5 ml of 2 M sodium hydroxide: the odour of ammonia is perceptible.

Melting range 188º to 191º (Appendix 4.3).

Water Not more than 0.5 per cent w/w (Karl Fischer Method, Appendix 4.12).

Heavy metals Not more than 10 ppm. Ignite gently 1.0 g until thoroughly charred, cool, add 2 ml of nitric acid and 5 drops of sulfuric acid, heat cautiously until white fumes are evolved, and ignite until the residue is free of carbon. Cool, add 2 ml of hydrochloric acid, evaporate to dryness on a water-bath and dissolve the residue in 20.0 ml of water. A 12.0-ml portion of the resulting solution complies with the “Limit Test for Heavy Metals” (Method I, Appendix 5.2). For the Standard Preparation, use lead standard solution (1 ppm Pb).

Sulfated ash Not more than 0.1 per cent w/w (Appendix 5.3); use 1.0 g.

Assay Place about 300 mg of Pyrazinamide, accurately weighed, in a 500-ml Kjeldahl flask, dissolve in 100 ml of water, and add 75 ml of 5 M sodium hydroxide. Connect the flask by means of a distillation trap to a wellcooled condenser, the delivery tube of which dips into 20 ml of a 4 per cent w/v solution of boric acid contained in a suitable receiver. Boil gently for 20 minutes, avoiding insofar as possible distilling any of the liquid, and then boil vigorously to complete the distillation of the ammonia. Cool the liquid in the receiver if necessary, add methyl red-methylene blue TS, and titrate with 0.1 M hydrochloric acid VS. Perform a blank determination, and make any necessary correction. Each ml of 0.1 M hydrochloric acid is equivalent to 12.31 mg of C5H5N3O.

MONOGRAPHS • PYRAZINAMIDE
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หมายเหตุ / Note : TP II 2011 PAGE 144-145