The behavior of a mixture of two crystalline compounds and a solvent can be visualized and explained by means of a ternary phase diagram. A ternary phase diagram shows how this mixture of components behaves thermodynamically. Although the construction of a ternary phase diagram may be quite laborious and requires at least a racemate and one pure (or properly enriched) enantiomer, it can give more insight if the crystallization process needs to be optimized.
In principle, the determination of the composition of the mother liquors is sufficient to make a phase diagram. However, important details will be missed if the composition of the solids and/or system compositions are not taken into account, for instance end-solid solution formation and hydrate/solvate formation.
Enantiomers can crystallize separately: each in a single crystal or together in one crystal. When a racemate crystallizes into two separate crystals of opposite handedness this is called a conglomerate. It is estimated that only 5–10% of all racemates crystallize as a conglomerate. More common (90–95%) is the formation of a racemic compound in which a racemate crystallizes in an ordered fashion. Rare (1%) is a solid solution where a crystal does not distinguish between (R)- and (S)-enantiomers. This crystal is then randomly packed. Typical ternary phase diagrams for these different crystallization behaviors are given here.
ter Horst et al. have proposed a straightforward phase diagram screening method to identify the solid state behavior of chiral compounds. With this method was determined the saturation temperature of a certain solution composition, instead of determining the saturation concentration at a certain temperature.
In their studies, ter Horst and Srisanga used the Crystal16 instrument to determine the saturation temperatures of the mixtures of enantiomers in different solvents. In the Crystal16, the clear and cloud points of different solutions were measured in parallel and automatically, based on turbidity measurement. A physical mixture of the enantiomeric pure and racemic crystalline phase was dissolved in the appropriate amount of solvent at a sufficiently high temThe Cryperature. The temperature at the point the suspension became a clear solution upon heating was taken as the saturation temperature of the measured sample, of which the composition was established beforehand. Determination of only one side of a binary or ternary phase diagram is sufficient to know the full phase diagram as they are symmetrical around 0.5. Enantiomers are known for their ability to rotate in opposite directions in plane-polarized light by equal amounts. Therefore, phase diagram screening method proposed by ter Horst and Srisanga is a fast way to obtain an indication of the solid state behavior and the phase diagram of chiral compounds.