The results of the sixth blind test of organic crystal structure prediction methods are presented and discussed, highlighting progress for salts, hydrates and bulky flexible molecules, as well as on-going challenges.

The separation of an enantiomer from a racemic mixture is of primary relevance to the pharmaceutical industry. The thermochemical properties of organic enantiopure and racemate crystals can be exploited to design an enantioselective crystallization process. The thermodynamic difference between the two crystal forms is accessible by two cycles which give the eutectic composition in solution. The "sublimation cycle" requires calculating the lattice energy and phonon frequencies of the crystal structures. Experimental results from heat capacity and other thermodynamic measurements of enantiopure and racemic crystals are compared with a variety of molecular and crystal structure-based calculations. This is done for three prototypes of pharmaceutical-like molecules with different degrees of molecular flexibility. Differences in crystal packing result in varying temperature-dependent heat capacities and affect the sublimation thermodynamics, relative solubility, and eutectic composition. Many simplifying assumptions about the thermodynamics and solubilities of the racemic and enantiopure crystals are critically evaluated. We show that calculations and experimental information using the sublimation cycle can guide the design of processes to resolve enantiomers by crystallization.

Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood.