Molecular basis for the stability relationships between homochiral and racemic crystals of tazofelone: a spectroscopic, crystallographic, and thermodynamic investigation

Abstract

Tazofelone (1) has been crystallized as two polymorphic racemic compounds (1a), designated I and II, and as an (S)-(−) enantiomorph (1b). These crystal forms have been characterized using FTIR and solid-state NMR spectroscopy, single crystal X-ray analysis, and differential scanning calorimetry. The stability relationship of the racemic polymorphs has been established as enantiotropic, with form II being low-temperature stable and form I being high-temperature stable (transition temperature 138 °C). These two forms have similar enthalpies, entropies, and free energies (thermodynamic stability), which may be related to their similar molecular conformations, hydrogen-bonding patterns, and crystal packing efficiencies. The racemic crystals are significantly more stable than the physical mixture of the enantiomorphs. The spontaneous conversion of the racemic crystals into the conglomerate is not feasible thermodynamically at any temperature (monotropy). The weak lattice of the enantiomorphs may result, in part, from the high energy conformers that are the building blocks of the enantiomorphs and weaker dipole–dipole interactions.