Crystallization Methods and Choice of Solvent

Classical crystallization methods have been reviewed by Guillory [18] and are listed in Table 5.2. Depending on the method, various degrees of freedom are possible. They include type of solvent or solvent mixture, cooling profile, temperature at start, temperature at end, concentration, pressure, humidity, surface-to-volume ratio, vessel type, and material of surface. Furthermore, many crystallization experiments are influenced by the initial solid-state form that is used (i.e., polymorph, solvate, hydrate, or the amorphous form) as this can affect the solubility and hence the degree of supersaturation. 

The choice of solvent is of particular importance. First, it has to be chosen such that the solubility is in a suitable range for the selected type of crystallization experiment (reasonably high solubility for cooling experiments, very low solubility in solvents used for precipitation, etc.). Second, it is important to use solvents with diverse physical properties in order to explore the whole parameter space of possible environments. In addition to molecular solvent-solute interactions, bulk properties of solvents such as viscosity may play a role. Gu et al. [19] examined 96 solvents in terms of 8 relevant solvent properties hydrogen bond acceptor propensity, hydrogen bond donor propensity, polarity/dipolarity, dipole moment, dielectric constant, viscosity, surface tension, and cohesive energy density (calculated from the heat of vaporization). Based on all 8 properties, the 96 solvents were sorted into 15 groups 

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