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Category Antiprotozoal (antimalarial).

Chloroquine Phosphate contains not less than 98.5 per cent and not more than 101.0 per cent of C₁₈H₂₆ClN₃.2H₃PO₄, calculated on the dried basis.

Description White or almost white, crystalline powder; hygroscopic.

Solubility Freely soluble in water; very slightly soluble in ethanol and in methanol.

Stability It discolours slowly on exposure to light.

Contra-indication
          1. It is contra-indicated in patients with retinal or visual field changes and hypersensitivity to 4-aminoquinolone compounds.
          2. It is contra-indicated for long-term therapy in children.

Warning
          1. Children and infants are especially sensitive to the 4-aminoquinolone compounds. Fatalities following accidental ingestion of relatively small doses and sudden death after intramuscular injections have been reported.
          2. It should not be administered parenterally in children because of the narrow therapeutic range in this age group.
          3. Certain strains of Plasmodium falciparum have become resistant to 4-aminoquinolone compounds including chloroquine. To improve efficacy and delay the onset of resistance, it should always be used in combination with another effective antimalarial.
          4. High dose or prolonged therapy can cause irreversible retinal or auditory damage, muscular weakness and blood dyscrasias. Acute overdosage can cause acute circulatory failure, convulsions, respiratory and cardiac arrest, and death.
          5. Rapid intravenous injection causes dizziness, nausea, disturbance of vision, and a transient fall of blood pressure.
          6. It should be used with caution in patients with severe hematopoietic, hepatic, neurological, or gastrointestinal disorder, glucose-6-phosphate dehydrogenase deficiency, alcoholism, psoriasis, or porphyria.
          7. Concurrent administration with potentially hemolytic drugs, 8-aminoquinolone compounds, bonemarrow suppressants, or dermatitis-causing medications, especially gold salts and phenylbutazone, should be avoided.
          8. Risk-benefit should be considered if it is to be used in pregnant or nursing women since it may cause fetal abnormalities (such as damage to the CNS, congenital deafness).

          Precaution Prolonged therapy requires periodic determinations of visual, auditory and hematopoietic functions, and examinations of knee and ankle reflexes in order to detect muscular weakness.

          Packaging and storage Chloroquine Phosphate shall be kept in tightly closed containers, protected from light.

Identification
          A. Dissolve 100 mg in 10 ml of water, add 2 ml of 2 M sodium hydroxide and extract with two 20-ml portions of chloroform, retaining the aqueous layer. Wash the chloroform extracts with water, dry with anhydrous sodium sulfate, evaporate to dryness, and dissolve the residue in 2 ml of chloroform. The infrared absorption spectrum of the chloroform solution is concordant with the spectrum obtained from Chloroquine Phosphate RS similarly treated (Appendix 2.1) or with the reference spectrum of Chloroquine.
          B. The ultraviolet absorption spectrum of a 0.0015 per cent w/v solution in 0.01 M hydrochloric acid, when observed between 240 and 350 nm, exhibits three maxima, at 257 nm, 329 nm and 343 nm; the absorbances of a 1-cm layer at these wavelengths are about 0.44, 0.48 and 0.55, respectively (Appendix 2.2).
          C. Dissolve 25 mg in 20 ml of water and add 8 ml of trinitrophenol TS: the precipitate, after washing successively with water, ethanol and ether, melts at about 207º (Appendix 4.3).
          D. Neutralize with 2 M nitric acid the aqueous layer obtained in Test A, add an equal volume of a 10 per cent w/v solution of ammonium molybdate, and warm: a yellow precipitate is produced.

Melting range It exists in 2 forms, one of which melts at about 195º and the other at about 218º (Appendix 4.3).

pH 3.8 to 4.3, in a 0.1 per cent w/v solution (Appendix 4.11).

Loss on drying Not more than 2.0 per cent w/w after drying at 105º to constant weight (Appendix 4.15).

Heavy metals Not more than 20 ppm. Dissolve 2.0 g in 10 ml of water. Add 5 ml of strong ammonia solution and shake with 40 ml of dichloromethane. Filter the aqueous layer and neutralize the filtrate with glacial acetic acid. Heat on a water-bath to eliminate dichloromethane, allow to cool and dilute to 20.0 ml with water. A 12.0-ml portion of the resulting solution complies with the “Limit Test for Heavy Metals” (Method II, Appendix 5.2). For the standard preparation, use lead standard solution (2 ppm Pb).

Related substances Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using silica gel GF254 as the coating substance.
          Test solution Dissolve 500 mg of the test substance in water and dilute to 10.0 ml with the same solvent.
          Reference solution 1 Dilute 1.0 ml of the Test solution to 100.0 ml with water.
          Reference solution 2 Dilute 5.0 ml of Reference solution 1 to 10.0 ml with water.
          Mobile phase Prepare a mixture of 10 volumes of diethylamine, 40 volumes of cyclohexane and 50 volumes of chloroform.
          Procedure Apply separately to the plate, 2 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 in the chromatogram obtained from Test solution, apart from the principal spot, is not more intense than the spot in the chromatogram obtained from Reference solution 1 (1.0 per cent) and not more than one such spot is more intense than the spot in the chromatogram obtained from Reference solution 2 (0.5 per cent).

Assay Dissolve about 200 mg of Chloroquine Phosphate, accurately weighed, in 50 ml of anhydrous glacial acetic acid. Titrate with 0.1 M perchloric acid VS, using crystal violet TS as indicator, to a blue 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 25.79 mg of C₁₈H₂₆ClN₃.2H₃PO₄.