Polymorph studies. A saturated sulfathiazole solution of a particular solvent or solvent mixture was prepared in a 20-mL scintillation vial in accordance with the solubility values determined at 60 °C from the experiments in "Solubility and crystal-yield studies" above. Solids were generated by cooling from 60 °C in a water bath to 25 °C in another water bath and intermittent shaking. Solids were immediately vacuum filtered and oven dried at 40 °C for 4 h. Polymorphism and crystal habits were determined by DSC, TGA, and OM.

DSC. A differential scanning calorimeter (DSC 7, Perkin Elmer, Norwalk, CT) was used to monitor thermal events during heating. The instrument was calibrated with indium (8–10 mg, 99.999% pure, extrapolated melting onset at 156.6 °C). All samples were run in crimped aluminum pans under a constant nitrogen purge. Each sample was heated at 10 °C/min.

TGA. A thermogravimetric analyzer (TGA 7, Perkin Elmer) was used to measure changes in the weight of a specimen while varying temperature in a controlled nitrogen atmosphere. About 2 to 3 mg of sample were placed on an open platinum pan and heated at 10 °C/min.

Results and discussion

The 24 solvents, arranged in ascending order by their total Hildebrand values, were n-heptane, xylene, p-xylene, ethyl acetate, toluene, methyl tert-butyl ether (MTBE), benzene, methyl ethyl ketone (MEK), chloroform, THF, DMA, acetone, 1, 4-dioxane, nitrobenzene, n-butyl alcohol, isopropyl alcohol (IPA), benzyl alcohol, acetonitrile, n-propanol, DMF, ethanol, dimethyl sulfoxide (DMSO), methanol, and water (24).

Sulfathiazole Form III crystals dissolved well in 11 solvents (labeled "good solvents"): MEK, THF, acetone, benzyl alcohol, acetonitrile, n-propanol, DMF, ethanol, DMSO, methanol, and water. The crystals dissolved only slightly in 13 solvents (labeled "bad solvents"): n-heptane, xylene, p-xylene, ethyl acetate, toluene, MTBE, benzene, chloroform, DMA, 1, 4-dioxane, nitrobenzene, n-butyl alcohol, and isopropyl alcohol. The crystals' solubility in these solvents was < 0.5 mg/mL at 25 °C.

Based on the solvent-miscibility studies of the solvent pairs of the 24 solvents, there were 38 gray boxes ÷ 2 = 19 immiscible pairs (because of the symmetry in Table II). The pure-solvent systems are represented by the 24 diagonal boxes in Table II. The form space (i.e., a probable condition of discovering a new polymorph) of the pure-solvent systems for our initial solvent screening was limited to the number of good single solvents, represented by the yellow boxes in Table II (24). Therefore, the probable condition of discovering a new polymorph for sulfathiazole was 11. However, if the good cosolvent systems (i.e., binary miscible mixtures of good solvents) are taken into account, the form space would be extended to the number of blue boxes in Table II ÷ 2 = 54. In addition, if the antisolvent systems (i.e., binary miscible mixtures of a good and a bad solvent) are also considered, the form space of the antisolvent systems would be calculated as the number of green boxes in Table II ÷ 2 = 126.