Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical

Five
anhydrate polymorphs (forms I–V)
and the isomorphic dehydrate (Hydehy) of dapsone (4,4′-diaminodiphenyl sulfone or DDS) were
prepared and characterized in an interdisciplinary experimental and
computational study, elucidating the kinetic and thermodynamic stabilities,
solid form interrelationships, and structural features of the known
forms I–IV, the novel polymorph form V, and Hydehy. Calorimetric
measurements, solubility experiments, and lattice energy calculations
revealed that form V is the thermodynamically stable
polymorph from absolute zero to at least 90 °C. At higher temperatures,
form II, and then form I, becomes the most
stable DDS solid form. The computed 0 K stability order (lattice energy
calculations) was confirmed with calorimetric measurements as follows, V (most stable) > III > Hydehy > II > I > IV (least stable). The discovery of form V was complicated
by the fact that the metastable but kinetically stabilized form III shows a higher nucleation and growth rate. By combining
laboratory powder X-ray diffraction data and ab initio calculations,
the crystal structure of form V (P21/c, Z′ = 4) was solved, with a high
energy DDS conformation allowing a denser packing and more stable
intermolecular interactions, rationalizing the formation of a high
Z′ structure. The structures of the forms I and IV, only observed from the melt and showing distinct packing
features compared to the forms II, III,
and V, were derived from the computed crystal energy
landscapes. Dehydration modeling of the DDS hydrate led to the Hydehy structure. This study expands
our understanding about the complex crystallization behavior of pharmaceuticals
and highlights the big challenge in solid form screening, especially
that there is no clear end point.