Pentamorphs of Acedapsone

Abstract

Acedapsone is a long acting prodrug of Dapsone, the diacetyl derivative of diaminophenyl sulfone. It exhibits superior bioavailability compared to the parent drug. Dapsone occupies a preeminent position in the treatment of leprosy since the 1940s. Surprisingly no X-ray crystal structure or polymorphs of acedapsone are reported. Five novel polymorphs of acedapsone are reported (I–V) of which crystal forms I and II are characterized by single X-ray diffraction. These novel polymorphs were crystallized from solution, slow cooling of the melt, and spray-drying of the powder. Solution crystallization afforded Acedapsone Forms I and II. Slow cooling of the melt phase resulted in an amorphous phase, which transformed to a new Form IV slowly at room temperature, and then to Form III. Fast cooling or quick quench of the amorphous solid gave Form I. Spray drying resulted in a new metastable polymorph V, but this polymorph also converted to Form III at room temperature after 6 h. In addition to five crystalline polymorphs of acedapsone, an amorphous phase was also obtained from the melt. XPac analysis of polymorphs I and II (space group P21/n and C2/c) showed 2D isostructurality, and Hirshfeld surface analysis revealed subtle differences in the molecular environment of the two crystal structures. The stability of five polymorphs by DSC, VT-PXRD, and upon heating in a sealed tube suggested that the kinetic stability order is Form I (most stable) > II > III > IV > V > amorphous (least stable), whereas competitive slurry and liquid-assisted grinding experiments gave the thermodynamic stability as Form II (most stable) > I > III > IV > V > amorphous (least stable). Solventless methods such as quench cooling of the melt and holding in a sealed tube at high temperature and pressure yielded the kinetically stable Form I. Spray drying of the powder gave metastable Forms III and V (which transformed over time), and slurry conditions gave the thermodynamic Form II. The pentamorphic system follows Ostwald’s law of stages. The role of solvent selection in the direct crystallization of Acedapsone polymorphs after diacetylation of Dapsone is also discussed.