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Diaphenylsulfone

Category Antibacterial (antileprosy); dermatitis herpetiformis suppressant.

          Dapsone contains not less than 98.0 per cent and not more than 102.0 per cent of C₁₂H₁₂N₂O₂S, calculated on the dried basis.

Description White or creamy white, crystalline powder; odourless.

Solubility Very slightly soluble in water; freely soluble in ethanol; soluble in acetone and in dilute mineral acids.

Contra-indication It is contra-indicated in patients with severe anemia; the anemia should be treated prior to initiation of dapsone therapy.

Warning
          1. It should be used with caution in patients with cardiac or pulmonary disease, with glucose-6-phosphate dehydrogenase deficiency and in pregnant women.
          2. It may cause hemolytic anemia, methemoglobinemia, leukopenia, gastro-intestinal upset, headache, nervousness, motor neuropathy, blurred vision, paresthesias and pruritus, hematuria, liver damage, jaundice, and rash.
          3. It should be used with caution in patients with methemoglobin reductase deficiency, hemoglobin M, or hepatic function impairment, and in those who are exposed to other drugs or agents that are capable of inducing hemolysis.
          4. Deaths from agranulocytosis, aplastic anemia, and other blood dyscrasias have been reported.

Precaution
          1. Periodic hemograms as well as liver function tests are recommended during the course of treatment.
          2. Discontinue the treatment when a lepra reaction appears, and consult the physician immediately.
          3. Dapsone therapy should be promptly discontinued if new or toxic dermatologic reactions, e.g. exfoliative dermatitis, toxic erythema, erythema-multiforme, toxic epidermal necrolysis, morbiliform and scarlatiniform eruptions, dapsone syndrome (hypersensitivity to sulfone including rash, fever, jaundice and eosinophilia), or Stevens-Johnson syndrome occur.
          4. Nursing mothers should discontinue nursing since it may potentially be tumorigenic and may cause drug-induced hemolytic anemia in neonates.

Additional information Although dapsone crosses the placenta, studies in humans have not shown that dapsone causes adverse effects on reproductive capacity or on the fetus.

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

Stability It is gradually degraded on exposure to a humid atmosphere, the decomposition being faster at higher temperatures. It becomes discoloured on exposure to light.

Identification
          A. The infrared absorption spectrum is concordant with the spectrum obtained from Dapsone RS (Appendix 2.1) or with the reference spectrum of Dapsone.
          B. The ultraviolet absorption spectrum of a 0.0005 per cent w/v solution in methanol, when observed between 230 and 350 nm, exhibits two maxima at 260 nm and 295 nm; the absorbances of a 1-cm layer at these wavelengths are about 0.36 and 0.60, respectively (Appendix 2.2).
          C. 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.
          D. A 2-ml portion of a 0.005 per cent w/v solution in 0.1 M hydrochloric acid yields the reaction characteristic of primary aromatic amines (Appendix 5.1).

Melting range 175º to 181º (Appendix 4.3).

Loss on drying Not more than 1.5 per cent w/w after drying at 105º for 3 hours (Appendix 4.15).

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

Selenium Not more than 30 ppm (Appendix 5.2). Use 100 mg and mix with 100 mg of magnesium oxide.

Chromatographic purity Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1), using a suitable high-performance thin-layer chromatographic plate coated with a 150- to 200-μm layer of chromatographic silica gel as the coating substance and a mixture of 60 volumes of chloroform, 15 volumes of acetone, 15 volumes of 1-butanol and 10 volumes of formic acid as the mobile phase.
          Standard solution A Dissolve Dapsone RS in methanol and mix to obtain a solution having a known concentration of about 12.5 mg per ml.
          Standard solution B Dilute Standard solution A quantitatively with methanol to obtain a solution having a known concentration of about 125 μg per ml.
          Standard solution C Dilute Standard solution B quantitatively with methanol to obtain a solution having a known concentration of about 62.5 μg per ml.
          Test solution Dissolve an accurately weighed quantity of the test substance in methanol to obtain a solution containing 12.5 mg per ml.
          Procedure (Note Prepare the solvent system fresh daily.) Apply separately 4 μl of each of the solutions to the plate. After removal of the plate, allow it to dry in air and spray with a 0.1 per cent w/v solution of 4- dimethylaminocinnamaldehyde in a mixture of equal volumes of glacial acetic acid and water. Examine the spots that are developed immediately, and compare the intensities of any secondary spots observed in the chromatogram of Test solution with those of the principal spot in the chromatogram of Standard solutions: no secondary spot from the chromatogram of Test solution is larger or more intense than the principal spot obtained from Standard solution C (0.5 per cent), and the sum of the intensities of all the secondary spots obtained from Test solution corresponds to not more than 1.0 per cent.

Assay Carry out the determination as described in the “High-pressure Liquid Chromatography” (Appendix 3.5).
          Mobile phase Transfer 100 ml of 2-propanol, 100 ml of acetonitrile, and 100 ml of ethyl acetate to a 1000-ml volumetric flask. Add pentane to volume without mixing. Mix and allow the mixture to cool to room temperature.
          Standard preparation Dissolve an accurately weighed quantity of Dapsone RS in methanol to obtain a solution having a known concentration of about 250 μg per ml. Pipette 5 ml of this solution into a 50-ml volumetric flask, dilute with Mobile phase to volume, and mix to obtain a solution having a known concentration of about 25 μg per ml.
          Assay preparation Transfer about 50 mg of Dapsone, accurately weighed, to a 200-ml volumetric flask. Dissolve in methanol, dilute with methanol to volume, and mix. Pipette 5 ml of this solution into 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 (30 cm × 3.9 mm) packed with porous silica microparticles (10 μm), (b) Mobile phase at a flow rate capable of giving the required resolution and a suitable elution time, 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 is not more than 2 per cent.
          Procedure Separately inject equal volumes (about 10 μl) of Standard preparation and Assay preparation into the chromatograph, record the chromatograms, and measure the responses of the major peaks.
          Calculation Calculate the content of C₁₂H₁₂N₂O₂S in the Dapsone taken, using the declared content of C₁₂H₁₂N₂O₂S in Dapsone RS.