Figure 2

T = 26 + 31 exp (-t ÷ 0.9)

where T = temperature (°C) and t = time (min). The relatively rapid decrease in temperature served as an ideal way to preserve kinetically induced polymorphs by a sudden surge of supersaturation (8). Solids produced were vacuum filtered at once and oven dried at 40 °C for 4 h. DSC and thermogravimetric analysis (TGA) were used mainly to determine the polymorphism of sulfathiazole solid samples. Optical microscopy (OM) was used for crystal-habit imaging.

Table I: Sources of solvents used in this experiment.

Active pharmaceutical ingredient. Sulfathiazole (Form III) white crystalline powders (C₉H₉N₃O₂S₂, MW: 255.31, m.p. = 201–204 °C, 98%, Lot: 410504/1 51804006) were purchased from Fluka (Buchs, Switzerland).

Solubility and crystal-yield studies. About 10 mg of sulfathiazole Form III crystals were weighed in a 20-mL scintillation vial. Drops of solvent or solvent mixture were titrated into the vial carefully by micropipette and shaken intermittently until all sulfathiazole Form III solids were dissolved. The solubility of sulfathiazole Form III solids at a given temperature was calculated as the weight of sulfathiazole Form III solids in a vial divided by the total volume of solvent or solvent mixture added to a vial. The solubility of sulfathiazole Form III solids in the same solvent or solvent mixture at 15, 25, 40, and 60 °C was determined. The crystal yield was calculated as the difference between the solubility at 60 °C and at 25 °C. All temperatures were maintained and controlled by a water bath. Despite the inherent inaccuracy (±20%) of measuring volume by sight, this method provided a rapid and robust technique for process scale-up (24).

Solvent-miscibility studies. Of the 24 solvents, about 1-mL portions of each solvent in a pair were shaken together for approximately 1 min in a 20-mL scintillation vial at 25 °C at 1 atm. Assuming that solvent miscibility was independent of the weight fraction of solvent, the solvent pair was considered to be miscible if no interfacial meniscus was observed after the contents of the vial were allowed to settle. If a meniscus was observed without apparent change in the volume of either solvent, the pair was regarded as immiscible (24).