Because solubility, polymorphism, crystallinity, and crystal habit are all solvent dependent, solvent screening is of fundamental and foremost importance to many chemical process industries, especially the pharmaceutical industry (4, 20–22). Recently, there has been increased interest in performing high-throughput polymorph screening in miniaturized scales using solvent evaporation (23–25). Because of the course of solid generation from a supersaturated solution by evaporation and the relatively small amount of the API used, however, these methods may not always correlate directly with the scale-up conditions in crystallization (e.g., a relatively large volume of solvent, temperature cooling, and stirring) and do not provide direct information about other simultaneous effects brought about by the solvent such as an API's solubility, crystallinity, and crystal habit.

This article promotes an alternative solvent-screening strategy that is tailor-made for the drug development and design of API solids processes. Under this initial screening strategy of pure-solvent systems, 23 kinds of solvent mostly useful for scale-up were chosen (26). The solubility of the API solute in each solvent at 15, 25, 40, and 60 °C was measured by gravimetric titration. The enthalpy and the entropy of solution for each solvent system were calculated. The solubility of the API in each solvent at 25 °C was plotted against the dielectric constant of various solvents, resulting in a characteristic solubility pattern that might serve as the fingerprint to identify a particular API. Although only pure-solvent systems were being considered in this study, the total "form space" for each API—that is, the total number of solid generation experiments in pure-solvent, cosolvent, and antisolvent systems— was also calculated on the basis of the number of good solvents for the API from the solubility studies and the number of miscible and immiscible solvent pairs from the miscibility investigations.