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Spiro[benzofuran-[2](3H),1’-2cyclohexene]-3,4’-dione, 7- chloro-2’,4,6-trimethoxy-6’-methyl-, (1’S-trans)-.

Category Antifungal.

      Griseofulvin contains not less than 97.0 per cent and not more than 102.0 per cent of C₁₇H₁₇ClO₆, calculated on the dried basis.

Description White to creamy white powder, in which particles of the order of 4 μm in diameter predominate; odourless.

Solubility Very slightly soluble in water; soluble in acetone, in dimethylformamide and in chloroform; sparingly soluble in methanol.

Contra-indication It is contra-indicated in pregnancy or in patients with porphyria, systemic lupus erythematosus or liver failure.

Warning

      1. It may cause headache, fatigue, dizziness, insomnia, gastro-intestinal distress, blood dyscrasias, renal insufficiency, hepatotoxicity, skin rash, urticaria, oral thrush, photosensitization, allergic reactions, and estrogenic-like effects in children.

      2. Concurrent use with alcohol, barbiturates or oral anticoagulants should be avoided.

      3. Overgrowth of yeasts or bacteria may accompany or follow long-term or too intensive treatment with griseofulvin.

Precaution

      1. Determination of complete blood count, serum creatinine concentration, hepatic function and urinalysis should be performed at periodic interval.

      2. Patients who are under treatment with griseofulvin should be warned to avoid exposure to intense natural or artificial sunlight.

Packaging and storage Griseofluvin shall be kept in well-closed containers. 

Labelling The label on the container states that griseofulvin is in microsize form.

Identification

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

      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. Dissolve 5 mg in 1 ml of sulfuric acid and add 5 mg of powdered potassium dichromate: a wine-red colour is produced.

Melting range 217º to 224º, after being dried (Appendix 4.3).

Clarity of solution A 7.5 per cent w/v solution in dimethylformamide is clear (Method II A, Appendix 4.1).

Particle size In a mortar, grind 10 mg with 10 drops of hydroxyethylcellulose TS. Add a further 3.50 ml of hydroxyethylcellulose TS and grind again. Transfer a drop of the suspension to a suitable counting chamber, 0.10 mm deep, place a cover glass over it, and examine under a microscope 10 fields of vision, each of 0.04-mm² area, using a magnification of 600º: not more than 30 crystals larger than 5 μm are visible in any field of vision.

Specific rotation +348º to +364º, calculated on the dried basis, determined in a 1 per cent w/v solution in dimethylformamide (Appendix 4.8).

Loss on drying Not more than 1.0 per cent w/w after drying about 100 mg accurately weighed, in a capillarystoppered bottle at a pressure not exceeding 0.7 kPa (about 5 Torr) at 60º for 3 hours (Appendix 4.15).

Sulfated ash Not more than 0.2 per cent w/w (Method II, Appendix 5.3).

Heavy metals Not more than 25 ppm (Method II, Appendix 5.2). Use 0.80 g; for the Standard Preparation, use lead standard solution (1 ppm Pb).

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).

      Mobile phase Prepare a mixture of 60 volumes of water, 35 volumes of acetonitrile and 5 volumes of tetrahydrofuran. Make adjustments if necessary.

      Standard preparation Dissolve an accurately weighed quantity of Griseofulvin RS in methanol to obtain a solution having a known concentration of about 1.25 mg per ml. Transfer 5.0 ml of this solution to a 50-ml volumetric flask, dilute with Mobile phase to volume, and mix. This solution contains about 125 μg of Griseofulvin RS in each ml.

      Assay preparation Transfer about 62 mg of Griseofulvin, accurately weighed, to a 50-ml volumetric flask, dissolve in and dilute with methanol to volume, and mix. Transfer 5.0 ml of this solution to a 50-ml volumetric flask, dilute with Mobile phase to volume, and mix.

      Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm × 4.6 mm) packed with nitrile groups chemically bonded to porous silica particles (3 to 10 μm), (b) Mobile phase at a flow rate of about 1 ml per minute and (c) an ultraviolet photometer set at 254 nm.

      To determine the suitability of the chromatographic system, 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.

      Procedure Separately inject equal volumes (about 20 μl) of Standard preparation and Assay preparation into the chromatograph, record the chromtograms and measure the responses for the major peaks.

      Calculation Calculate the content of C₁₇H₁₇ClO₆ in the Griseofulvin taken, using the declared content of C₁₇H₁₇ClO₆ in Griseofulvin RS.