Molecular Level Understanding of the Reversible Phase Transformation between Forms III and II of Dapsone

The reversible solid-state phase transformation between the neat forms II and III of dapsone (DDS) was studied using thermal analytical methods, variable temperature X-ray diffraction and solid-state modeling at the electronic level. The first order III ↔ II phase transformation occurs at 78 ± 4 °C with a heat of transition of 2 kJ mol^-1 and a small hysteresis. The two isosymmetric polymorphs (both P2₁2₁2₁) differ only in movement of layers of molecules and show a small variation in conformation. The combination of variable-temperature single-crystal structure determinations and pair-wise intermolecular energy calculations allowed us to unravel the single-to-single crystal transformation at a molecular level, to estimate the molecular contributions to the heat of transformation and to rationalize why the room and low temperature form III is the less dense polymorphic form, which is a rare phenomenon in enantiotropically related pairs of polymorphs in molecular crystals.