Comparing the solubility of sulfathiazole Form III crystals in each solvent at 25 °C (see Figure 3) with the solvent properties,
the authors found that the dispersion-force contribution (Hansen dispersion parameter d) was small in all cases, but the polar-force contribution (Hansen polar parameter p) and the hydrogen-bonding contribution (Hansen hydrogen-bonding parameter h) were critical (24). The solvent needed relatively strong polar force, hydrogen bonding, or both to achieve acceptable solubility
by disrupting the hydrogen-bonded network in crystalline sulfathiazole (9). This criterion is shown by the fact that the highest
solubility was about 0.03 g/mL sulfathiazole Form III crystals in ternary solvent mixtures of acetonitrile, n-propanol, and water with mole fraction ratios of (45:10:45) (see Figure 6e) and (50:0:50) (see Figure 6a) at 25 °C. Acetonitrile
and water individually had high values of 18.0 MPa¼ and 42.3 MPa¼ for δp and δh at 25 °C, respectively (24). Only when they were both blended at equally high mole fractions could the resultant mixed-solvent
system exhibit relatively high solubility (see Figure 5). In this case, the solubility of the solvent mixtures (see Figure
5) was generally better than that of the single-solvent systems (see Figure 3).
Solids generated by the cooling method from the 11 good solvents (i.e., the yellow boxes in Table II) and 13 solvent mixtures
(i.e., points 4–16 in Figure 2) were isolated and then analyzed by DSC and TGA. Although sulfathiazole forms solvates, TGA
showed that none of the solids were solvates or hydrates because no weight loss occured from 50 to 205 °C for all solids (19).
Based on the five general melting points of Forms I–V sulfathiazole crystals at around 203, 198, 175, 166 (broad), and 148
°C (broad), respectively, DSC responses in Figure 8 illustrated the various sulfathiazole crystal forms grown in the 11 single
solvents: MEK (Forms I, III, and V), THF (Form III), acetone (Forms I and V), benzyl alcohol (Form I), acetonitrile (Forms
I, III, and IV), n-propanol (Forms I and V), DMF (Form III), ethanol (Forms I, III, IV, and V), DMSO (Forms I, III, and V), methanol (Forms
I, III, and V), and water (Forms I and III) (15).
Form II was not observed at all in any solvent. The endotherm at 203 °C was the melting point of Form I, which might have
been produced by the enantiotropic transformation of Forms II, III, IV (and possibly V) upon heating in the DSC (27). For
example, a specimen of pure Form III generated in water that was free from seeds of Form I surpassed the transition point,
melted at its melting point, and immediately underwent exothermic recrystallization, as indicated by the exotherm at about
182 °C in Figure 8k. But sometimes crystals did not resolidify as polymorphs with higher melting points when the system was
kinetically trapped, as in the cases of sulfathiazole solids grown in THF and DMF (see Figures 8b and 8g) (28, 29).