Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation, and structural studies

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization . The melting points and enthalpies of fusion of a number of chiral drugs a nd their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantio mers and racemic species, the enthalpy, entropy and Gibbs free energy of th e racemic species were derived from the thermal data. The Gibbs free energy of formation, Delta G(T1)degrees, is always negative for a racemic compoun d, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the p rocess. For a racemic conglomerate, the entropy of mixing in the liquid sta te is close to the ideal value of R In 2 (1.38 cal.mol(-1).K-1). Pseudorace mates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the h omochiral species, Delta G(T1)degrees, is approximately zero, indicating th at the racemic compound and racemic conglomerate possess similar relative s tabilities. The powder X-ray diffraction patterns and C-13 solid-state nucl ear magnetic resonance spectra are valuable for revealing structural differ ences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreeme nt for identifying the nature of the racemic species.