The crystal habits and length–breadth aspect ratios of sulfathiazole crystals produced by the 11 pure single solvents and
13 solvent mixtures of acetonitrile, n-propanol, and water by cooling are shown in Figures 10 and 11, respectively. In general, Form I possessed a needle-like morphology.
Form II had a cuboid morphology. The morphology of Form III was a truncated hexagon and Form IV had a plate-like hexagonal
morphology (9). If crystal habits alone are used as a visual guide, the major phases grown from the 11 pure single solvents
were: Form I in MEK, acetone, benzyl alcohol, acetonitrile, and n-propanol; Form III in THF, DMF, ethanol, DMSO, and water; and Form IV in methanol. Clearly, the observation that Form I appeared
with the same crystal habit from more than one solvent suggested that none of the available solvent–surface interactions could
inhibit the addition of sulfathiazole molecules to the {010} face (9). A similar conclusion could be drawn for Form III and
its fast-growing {110} face (9).
Figure 8
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In the solvent mixture systems of acetonitrile:n-propanol:water, Form I was the major phase in the needle-like crystals grown in the solvent mixtures of (50:50:0), (45:45:10),
(60:20:20), (0:50:50), and (50:0:50), judging by the crystal habits. Form III was the major phase in the truncated hexagonal
crystals produced by mixtures of (80:10:10), (10:80:10), (33:33:33), (20:20:60), and (10:10:80). Form IV was the major phase
in the plate-like hexagonal crystals generated in the solvent mixtures of (10:80:10), (10:45:45), (45:10:45), and (10:10:80).
Unlike the crystal habits in the pure solvent systems, not all of the crystal habits in the solvent mixtures were well defined.
Figure 9
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The authors speculated that the lack of definition was caused by the presence of various polymorphs in a crystal, as indicated
by the DSC scans (see Figures 8 and 9), and not by the solvent–surface interactions. The average size of crystals grown in
the solvent mixtures was larger than those grown in pure solvent systems. Because the DSC traces in Figures 8 and 9 were derived
from the sulfathiazole crystals produced by spontaneous nucleation, if the high crystal yield given by a solvent mixture is
desired, the polymorphic purity of sulfathiazole can be ensured by seeding (3).
Conclusion
Figure 10
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Successful large-scale preparation of fine chemicals, and the manufacture of pharmaceuticals in particular, depends heavily
on the solubility, crystal yield, and polymorphism of solid compounds and active pharmaceutical ingredients. The cocktail
solvent screening method is a simple and inexpensive technique on a laboratory scale. It should be implemented together with
the initial solvent screening approach to enhance the solubility of green solvents, increase crystal yield, and optimize the
chances of finding the number of polymorphs by coupling with DSC.
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