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Category Antibacterial; antiprotozoal.

      Sulfamethoxazole and Trimethoprim Oral Suspension contains not less than 90.0 per cent and not more than 110.0 per cent of the labelled amounts of C₁₀H₁₁N₃O₃S and C₁₄H₁₈N₄O₃.

Strength available 200 mg of sulfamethoxazole and 40 mg of trimethoprim per 5 ml.

Dose Adults and children 40 kg of body weight and over----Antibacterial (systemic): 800 mg of sulfamethoxazole and 160 mg of trimethoprim every 12 hours.

      Antiprotozoal----Pneumocystis carinii pneumonia (PCP)----

      Treatment: 18.75 to 25 mg of sulfamethoxazole and 3.75 to 5 mg of trimethoprim per kg of body weight every 6 hours for 14 to 21 days.

      Prophylaxis: 800 mg of sulfamethoxazole and 160 mg of trimethoprim once a day.

      Acceptable alternative dosing schedules include: 800 mg of sulfamethoxazole and 160 mg of trimethoprim three times a week (e.g., Monday, Wednesday, Friday); or 400 mg of sulfamethoxazole and 80 mg of trimethoprim once a day.

      Children up to 40 kg of body weight and infants 2 months of age and over----Antibacterial (systemic): 20 to 30 mg of sulfamethoxazole and 4 to 6 mg of trimethoprim per kg of body weight every 12 hours.

      Antiprotozoal----PCP----

      Treatment: 18.75 to 25 mg of sulfamethoxazole and 3.75 to 5 mg of trimethoprim per kg of body weight every 6 hours for 14 to 21 days.

      Prophylaxis----Children 4 weeks of age and over: 375 mg of sulfamethoxazole per m2 of body surface area (Appendix 1.17) and 75 mg of trimethoprim per m2 of body surface area twice a day, three times a week on consecutive days (e.g., Monday, Tuesday, Wednesday).

      Acceptable alternative dosing schedules include: 750 mg of sulfamethoxazole per m2 of body surface area and 150 mg of trimethoprim per m2 of body surface area as a single daily dose three times a week on consecutive days (e.g., Monday, Tuesday, Wednesday); or 375 mg of sulfamethoxazole per m2 of body surface area and 75 mg of trimethoprim per m2 of body surface area twice a day, 7 days a week; or 375 mg of sulfamethoxazole per m2 of body surface area and 75 mg of trimethoprim per m2 of body surface area twice a day, three times a week on alternate days (e.g., Monday, Wednesday, Friday).

(Note PCP prophylaxis is recommended for all infants born to HIV-infected mothers starting at 4 weeks of age, regardless of their CD4 lymphocyte counts. However, if the infant is receiving zidovudine during the first 6 weeks of life for the prevention of perinatal HIV transmission, sulfamethoxazole and trimethoprim combination prophylaxis should be delayed until zidovudine is discontinued at 6 weeks of age, to reduce the chance of anemia that may occur if these two medications are given concurrently.)

Contra-indication; Warning; Precaution; Additional information See under Sulfamethoxazole, p. 152 and Trimethoprim, p. 166.

Packaging and storage Sulfamethoxazole and Trimethoprim Oral Suspension shall be kept in tightly closed containers, protected from light.

Identification

      A. In tests A and B for Chromatographic purity, the respective Test preparations exhibit spots whose Rf values correspond to those spots produced by the Standard preparations of Trimethoprim RS and Sulfamethoxazole RS (Rf about 0.7).

      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.

pH 5.0 to 6.5 (Appendix 4.11).

Ethanol content Not more than 0.5 per cent v/v (Method II, Appendix 6.5).

Chromatographic purity

      TEST A (FOR TRIMETHOPRIM DEGRADATION PRODUCT) Not more than 0.5 per cent w/w. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1).

      Solvent mixture Mix 4 volumes of chloroform with 1 volume of methanol.

      Mobile phase Prepare a mixture of 80 volumes of chloroform, 20 volumes of methanol and 3 volumes of strong ammonia solution.

      Standard solution A Prepare a solution of Trimethoprim RS in Solvent mixture to contain 20.0 mg per ml.

      Standard solution B Dilute an accurately measured volume of Standard solution A quantitatively with Solvent mixture to obtain a solution having a known concentration of 100 μg per ml.

      Test solution Transfer an accurately measured volume of the oral suspension, containing about 40 mg of trimethoprim, to a separator. Extract with three 25-ml portions of Solvent mixture, collecting the extracts in a 125-ml conical flask. Evaporate the combined extracts to dryness on a water-bath with the aid of a current of air. Dissolve the residue in 2.0 ml of Solvent mixture, and then centrifuge. 

      Procedure Apply separately 5 μl each of Test solution, Standard solution A, and Standard solution B, to a plate coated with silica gel G. After removal of the plate, allow it to dry in air and examine under ultraviolet light (254 nm): trimethoprim produces a spot at an Rf value of about 0.7, and the trimethoprim degradation product can be seen at an Rf value of about 0.3 to 0.5. Any spot from Test solution at an Rf value of about 0.3 to 0.5 is not greater in size and intensity than the spot produced by Standard solution B at an Rf value of about 0.7.

      TEST B (FOR SULFANILAMIDE/SULFANILIC ACID, AND SULFAMETHOXAZOLE N4-GLUCOSIDE) Not more than 0.5 per cent w/w of sulfanilamide, 0.3 per cent w/w of sulfanilic acid and 3.0 per cent w/w of sulfamethoxazole N4-glucoside. Carry out the test as described in the “Thin-layer Chromatography” (Appendix 3.1).

      Ethanol-methanol mixture Mix 19 volumes of absolute ethanol and 1 volume of methanol.

      Mobile phase Prepare a mixture of 25 volumes of Ethanol-methanol mixture, 25 volumes of n-heptane, 25 volumes of chloroform, and 7 volumes of glacial acetic acid.

      Modified Ehrlich’s reagent Dissolve 100 mg of 4-dimethylaminobenzaldehyde in 1 ml of hydrochloric acid and dilute with ethanol to 100 ml.

      Standard solution A Weigh 20.0 mg of Sulfamethoxazole RS into a 10-ml volumetric flask, dissolve in 1 ml of strong ammonia solution, dilute with methanol to volume, and mix.

      Standard solution B Weigh 10.0 mg of Sulfanilamide RS into a 50-ml volumetric flask, dissolve in 5 ml of strong ammonia solution, and dilute with methanol to volume. Pipette 5 ml of this solution into a 100-ml volumetric flask, add 10 ml of strong ammonia solution, and dilute with methanol to volume.

      Standard solution C Weigh 10.0 mg of Sulfanilic Acid RS into a 50-ml volumetric flask, dissolve in 5 ml of strong ammonia solution, and dilute with methanol to volume. Pipette 3 ml of this solution into a 100-ml volumetric flask, add 10 ml of strong ammonia solution, and dilute with methanol to volume.

      Standard solution D Weigh 3.0 mg of Sulfamethoxazole N4-glucoside RS into a 50-ml volumetric flask, dissolve in 5 ml of strong ammonia solution, and dilute with methanol to volume.

      Test solution Transfer an accurately measured volume of the oral suspension, containing 200 mg of sulfamethoxazole, to a 100-ml volumetric flask containing 10 ml of strong ammonia solution, and add 50 ml of methanol. Shake for 3 minutes, and dilute with methanol to volume. Centrifuge a portion of the solution for 3 minutes.

      Procedure Apply separately 50 μl each of Test solution and Standard solutions A, B, C, and D to a plate coated with silica gel G. Place the plate in an unsaturated chromatographic chamber. After removal of the plate, allow it to dry in air, spray with Modified Ehrlich’s reagent, and allow the plate to stand for 15 minutes: sulfamethoxazole produces a spot at an Rf value of about 0.7. Any spots from Test solution at an Rf value of about 0.5, 0.1 and 0.3 are not greater in size and intensity than spots produced by Standard solutions B, C and D, respectively.

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

      Mobile phase Mix 1400 ml of water, 400 ml of acetonitrile, and 2.0 ml of triethylamine in a 2000-ml volumetric flask. Allow to equilibrate to room temperature, and adjust with 0.2 M sodium hydroxide or diluted glacial acetic acid (1 in 100) to a pH of 5.9±0.1. Dilute with water to volume. Make adjustments if necessary.

      Standard preparation Dissolve accurately weighed quantities of Trimethoprim RS and Sulfamethoxazole RS in methanol, and dilute quantitatively with methanol to obtain a solution containing, in each ml, about 0.32 mg and 0.32F mg, respectively, F being the ratio of the labelled amount, in mg, of sulfamethoxazole to the labelled amount, in mg, of trimethoprim in the dosage form. Transfer 5.0 ml of this solution to a 50-ml volumetric flask, dilute with Mobile phase to volume, and mix to obtain a Standard preparation having known concentrations of about 0.032 mg of Trimethoprim RS per ml and 0.032F mg of Sulfamethoxazole RS per ml.

      Assay preparation Transfer an accurately measured volume of Sulfamethoxazole and Trimethoprim Oral Suspension, containing about 80 mg of sulfamethoxazole, to a 50-ml volumetric flask with the aid of about 30 ml of methanol. Sonicate the mixture for about 10 minutes with occasional shaking. Allow to equilibrate to room temperature, dilute with methanol to volume, mix, and centrifuge. Transfer 5.0 ml of the supernatant liquid to a second 50-ml volumetric flask, dilute with Mobile phase to volume, mix, and filter.  

      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 2 ml per minute, and (c) an ultraviolet photometer set at 254 nm. Chromatograph Standard preparation, and record the peak responses as directed under Procedure: the resolution factor between the sulfamethoxazole and trimethoprim peaks is not less than 5.0, and the relative standard deviation for replicate injections is not more than 2.0 per cent. The relative retention times are about 1.8 for sulfamethoxazole and 1.0 for trimethoprim.

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

      Calculation Calculate the content of C₁₀H₁₁N₃O₃S and C₁₄H₁₈N₄O₃ in the Oral Suspension using the declared content of C₁₀H₁₁N₃O₃S in Sulfamethoxazole RS and C₁₄H₁₈N₄O₃ in Trimethoprim RS, respectively.

Other requirements Comply with the requirements described under “Oral Liquids” (Appendix 1.16).