Thermochemistry of Racemic and Enantiopure Organic Crystals for Predicting Enantiomer Separation

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.