Within the pharmaceutical industry, the chemical synthesis of chiral substances provides mostly racemates with 50:50 mixtures of the enantiomers. On the other hand, most of the chiral drugs are produced in the form of single enantiomers; often only one of the enantiomers shows the desired bioavailability. Hence, enantiomeric separation is an important task in pharmaceutical development. Moreover, on the basis of the benefits of single enantiomers and the size of the chiral market, production of enantiomeric pure substances via separation processes such as crystallization has become very profitable.
According to J. Jacques et al, chiral systems are divided into (1):
The choice of an adequate solvent for the crystallization process is mostly related to the final separation process, which directly influences the final yield, the crystal morphology, the appearance of solvates or polymorphic varieties, and the purity of the product. Furthermore, the metastable zone width (MSZW) is also related to the choice of the solvent and therefore a very important key parameter for crystallization processes.
Chiral solvents are expected to be able to create selective interactions with a chiral solute, which facilitates a differentiation between the two single enantiomers (2,3). This discrimination can provide selective kinetic or solution thermodynamic effects, which might be useful for the separation of enantiomers.
Seidel-Morgenstern et al. studied the usage of chiral task-specific solvents for the resolution of the compound-forming system, mandelic acid (4). Mandelic acid has a long history of use in the medical community as an antibacterial, particularly in the treatment of urinary tract infections. Because structural similarities could enhance the chances of asymmetric behavior, several esters of (S)-mandelic acid were synthesized, and tested by Seidel-Morgenstern et al. With regard to a resolution process, their studies showed that the yield of the less soluble (S)-mandelic acid might be increased by exploitation of the wide MSZW of the more soluble (R)-mandelic acid. Additionally, it should be possible to crystallize (S)-mandelic acid under conditions where (R)-mandelic acid is already supersaturated but still in the metastable zone.
Determination of solubility was performed by using the temperature variation method on a Crystal16® instrument. The Crystal16® is one of the smallest scale commercial crystallizer with integrated turbidity measurement to determine cloud and clear points and thus the MSZW. The temperature variation and solvent addition methods are two dynamic methods for effective and reproducible solubility data generation. These methods can be easily applied by making use of the turbidity probes integrated in the Crystal16® and particle viewer cameras of the Crystalline™ instruments.
In general, it can be expected that a chiral solvent can discriminate two enantiomers by creating some weak interactions between the solvent and the substrate molecules forming diastereomeric complexes with different physical properties. This may lead to either asymmetry in the solubility phase diagrams or selective kinetic effects which can be employed for resolution purposes.