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

Tazofelone (1) has been crystallized as two polymorphic racemic compounds ( 1a), designated I and II, and as an (S)-(-) enantiomorph (1b). These crysta l 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 en antiotropic, with form II being low-temperature stable and form I being hig h-temperature stable (transition temperature 138 degrees C). These two form s have similar enthalpies, entropies, and foe energies (thermodynamic stabi lity), which may be related to their similar molecular conformations, hydro gen-bonding patterns, and crystal packing efficiencies. The racemic crystal s are significantly more stable than the physical mixture of the enantiomor phs. The spontaneous conversion of the racemic crystals into the conglomera te is not feasible thermodynamically at any temperature (monotropy). The we ak lattice of the enantiomorphs may result, in part, from the high energy c onformers that are the building blocks of the enantiomorphs and weaker dipo le-dipole interactions.