Table II: The 24 3 24 form space of sulfathiazole Form III crystals at 25 8C.
Currently, the total form space should then be at least equal to 11 + 54 + 126 = 191. The total form space is expected to
expand dramatically if various solvent compositions of binary mixtures, temperatures, and ternary solvent systems are also
considered (14). Solid generation by cooling can be applied in the yellow and blue regions in the form space (see Table II)
if solubility curves are available. However, isothermal condition is usually employed if solid generation is achieved by adding
antisolvent to the green domain (see Table II). Generally, no attempts are made to generate solids in the regions of immiscible
solvent pairs (gray boxes), bad solvents (red boxes), and cosolvents of bad solvents (white boxes) (i.e., binary mixture of
miscible bad solvents) in the form space (see Table II).
Therefore, only 11 solubility curves of sulfathiazole Form III crystals in 11 kinds of good solvent, based on their solubility
at 15, 25, 40, and 60 °C, were constructed and grouped by their solubility ranges for ease of comparison (see Figure 3). The
crystal yield was calculated as the solubility difference between 60 and 25 °C, based on Figure 3 for each solvent (see Figure
4). Although solvents such as DMF and DMSO gave high crystal yields, they are environmentally harmful (6).
Since the 24 × 24 form space in Table II did not take the solvent compositions and the ternary solvent mixtures into account,
the authors developed a "triangular form space" for given ternary solvent mixtures. Three of the 11 good solvents (acetonitrile,
n-propanol, and water) were used to concoct three different binary mixtures and 10 different ternary mixtures (see Figure 2).
Consequently, there were 3 + 10 = 13 combinatorial mixtures in total. The compositions of each mixture were expressed by mole
fraction ratios of acetonitrile:n-propanol:water. The 13 points and three single solvents were coordinated on a triangular graph (see Figure 2). The corresponding
16 solubility curves of sulfathiazole Form III crystals were constructed and grouped by their solubility ranges at 15, 25,
40, and 60 °C for ease of comparison (see Figure 5). Solubility curves at 15, 25, 40, and 60 °C for the binary and ternary
mixtures as a function of mole fractions are illustrated in Figure 6. The crystal yield, based on the solubility difference
from 60 to 25°C in Figure 5, is shown in Figure 7. The crystal yields of the solvent mixtures such as (80:10:10), (60:20:20),
(45:10:45), and (50:0:50) were much higher than that of acetonitrile, n-propanol, and water individually, and almost as high as that of THF.