At first, the solubility of sulfathiazole in each solvent or combination of solvent mixtures at 15, 25, 40, and 60 °C was
measured by gravimetric titration (see Figure 2). This method did not require any calibration and was more robust than weighing
the dry-residue mass, which might prompt the formation of sulfathiazole solvates during the drying process (11, 19). The crystal
yield was estimated by finding the solubility difference between 60 and 25 °C for each solvent or solvent mixture. Solid generation
of sulfathiazole in each solvent or solvent mixture was then achieved in a 20-mL scintillation vial by gentle shaking and
cooling from 60 °C in a water bath to 25 °C in another water bath. The cooling rate of a solution with a volume of less than
20 mL was almost independent of the volume and the nature of a solvent. The cooling profile could be approximated by an exponential
decay determined experimentally as:
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.
Materials and methods
Table I lists the solvents used in this study and the companies that provided them. Reversible osmosis (RO) water was clarified
with a water purification system (Milli-RO Plus, Millipore, Billerica, MA).
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).
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).