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Category Antiprotozoal (antimalarial).

      Quinine Sulfate is the sulfate of an alkaloid, quinine, obtained from the bark of various species of Cinchona. It contains not less than 99.0 per cent and not more than the equivalent of 101.0 per cent of total alkaloids, calculated as (C₂₀H₂₄N₂O₂)2.H₂SO₄, on the dried basis.

Description White, fine, needle-like crystals, usually lusterless, making a light and readily compressible mass; odourless.

Solubility Slightly soluble in water, in chloroform and in ethanol; sparingly soluble in water at 100º; freely soluble in ethanol at 80º, and in a mixture of 2 volumes of chloroform and 1 volume of absolute ethanol; very slightly soluble in ether.

Stability It darkens on exposure to light. It is incompatible with alkalis and their carbonates, iodides and tannic acid.

Contra-indication It is contra-indicated in patients with severe glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, optic neuritis, tinnitus, history of blackwater fever and thrombocytopenic purpura.

Warning

      1. It should be used with caution in patients with myasthenia gravis, hypoglycemia, atrial fibrillation or other serious heart diseases.

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

Precaution

      1. Quinine should be stopped immediately if evidence of hemolysis appears. Concurrent administration with oral anticoagulants should also be avoided.

      2. The repeated administration of quinine in full therapeutic doses may give rise to cinchonism, characterized by tinnitus, headache, nausea, abdominal pain, skin rashes, disturbed vision, and blindness.

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

Identification

      A. In the test for Chromatographic purity below, the principal spot in the chromatogram obtained from Test solution corresponds in position, colour and intensity to the principal spot in the chromatogram obtained from Standard preparation.

      B. Dissolve 5 mg in 5 ml of water and add 4 drops of bromine TS and 1 ml of 2 M ammonia: an emeraldgreen colour is produced. 

      C. Dissolve 100 mg in 3 ml of 1 M sulfuric acid and dilute to 100 ml with water: an intense blue fluorescence develops which disappears almost completely on the addition of 0.1 ml of hydrochloric acid.

      D. It yields the reactions characteristic of sulfates (Appendix 5.2).

pH 5.7 to 6.6, in a 1 per cent w/v suspension (Appendix 4.11).

Specific rotation –235º to –245º, determined in a 2.0 per cent w/v solution in 0.1 M hydrochloric acid (Appendix 4.8).

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

Loss on drying Not less than 3.0 per cent w/w and not more than 5.0 per cent w/w after drying at 105º to constant weight (Appendix 4.15). 

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

Chloroform-ethanol-insoluble substances Not more than 0.1 per cent w/w. Warm 2.0 g with 15 ml of a 8 mixture of 2 volumes of chloroform and 1 volume of absolute ethanol at about 50º for 10 minutes. Filter through a tared, sintered-glass filter, using gentle suction. Wash the filter with five 10-ml portions of the chloroform-ethanol mixture, dry at 105º for 1 hour, and weigh: the weight of the residue does not exceed 2 mg.

Chromatographic purity Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel G as the coating substance.

      Standard preparation Prepare a solution of Quinine Sulfate RS in ethanol (50 per cent) to contain 6 mg per ml.

      Diluted standard preparation Dilute a portion of Standard preparation with ethanol (50 per cent) to a concentration of 0.06 mg per ml.

      Related substances preparation Prepare a solution in ethanol (50 per cent) containing, in each ml, 0.05 mg each of Quininone RS (corresponding to 0.06 mg of quininone sulfate) and 0.10 mg of cinchonidine (corresponding to 0.12 mg of cinchonidine sulfate).

      Test solution Prepare a solution of the test substance in ethanol (50 per cent) to contain 6 mg per ml.

      Mobile phase Prepare a mixture of 5 volumes of chloroform, 4 volumes of acetone and 1 volume of diethylamine.

      Procedure Apply separately to the plate, 10 μl of each of the solutions. The solvent chamber being used without previous equilibration. After removal of the plate, allow it to dry in air, spray with glacial acetic acid and examine under ultraviolet light (366 nm). Any spot produced by Test solution at the Rf value of a spot produced by Related substances preparation is not greater in size or intensity than that corresponding spot. Apart from these spots and from the spot appearing at the Rf value of quinine sulfate, any additional fluorescent spot is not greater in size or intensity than the spot of Diluted  standard preparation. Spray the plate with potassium iodoplatinate TS. Any spot produced by Test solution is not greater in size or intensity than a corresponding spot from Related substances preparation.

Limit of dihydroquinine sulfate Not more than 10.0 per cent w/w of dihydroquinine. Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).

      Methanesulfonic acid solution Add 35.0 ml of methanesulfonic acid to 20.0 ml of glacial acetic acid, dilute with water to 500 ml, and mix.

      Diethylamine solution Dissolve 10.0 ml of diethylamine in water to obtain 100 ml of solution.

      Mobile phase Prepare a suitable filtered and degassed mixture of 43 volumes of water, 5 volumes of acetonitrile, 1 volume of Methanesulfonic acid solution, and 1 volume of Diethylamine solution. Adjust with Diethylamine solution to a pH of 2.6 if found to be lower.

      System suitability preparation Transfer about 10 mg each of quinine sulfate and dihydroquinine to a 50-ml volumetric flask. Dissolve in about 5 ml of methanol, dilute with Mobile phase to volume, and mix.

      Test solution Transfer about 20 mg of the test substance to a 100-ml volumetric flask, dissolve in and dilute with Mobile phase to volume, and mix. 

      Chromatographic system The chromatographic procedure may be carried out using (a) a stainless steel column (30 cm × 3.9 mm) packed with octadecylsilane chemically bonded to porous silica or ceramic microparticles (3 to 10 μm), (b) Mobile phase at a flow rate of about 1 ml per minute, and (c) an ultraviolet photometer set at 235 nm.

      To determine the suitability of the chromatographic system, chromatograph System suitability preparation, and record the peak responses as directed under Procedure: the relative retention times are about 0.67 for quinine and 1.0 dihydroquinine. The resolution between the quinine and dihydroquinine peaks is not less than 1.2. The relative standard deviation for the peak responses of quinine is not more than 2.0 per cent.

      Procedure Inject about 50 μl of the Test solution into a chromatograph, record the chromatogram, and measure the responses for the major peaks. The response of the dihydroquinine peak is not greater than one-ninth that of the quinine peak.

Assay Dissolve about 300 mg of Quinine Sulfate, accurately weighed, in a mixture of 10 ml of chloroform and 20 ml of acetic anhydride. Titrate with 0.1 M perchloric acid VS, using crystal violet TS as indicator, to a bluegreen end-point, 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 24.90 mg of (C₂₀H₂₄N₂O₂)₂.H₂SO₄.