Reversible, two-step single-crystal to single-crystal phase transitions between desloratadine forms I, II, and III

Abstract

Single-crystal to single-crystal polymorphic transformations in molecular solids are relatively rare, with changes in crystal structure more commonly leading to destruction of the parent crystal. However, the structural basis for such transitions is of considerable interest given the changes in material properties that can result. The antihistamine desloratadine displays a two-step, reversible single-crystal to single-crystal phase transition during heating/cooling cycles between three conformational polymorphs: the low temperature form I, a polytypic intermediate form II, and the high temperature form III. The two-step transition involves a sequential flipping of the piperidine rings of desloratadine molecules in the crystals, which induce reversible micrometer-scale contraction on heating and expansion on cooling of the largest face of a desloratadine single crystal. Distinct, slow-moving phase boundaries, originating on the (001) face of the crystal, were observed sweeping through the entire crystal in hot-stage microscopy, suggesting a single nucleation event. Computational spectroscopy, using periodic DFT-D phonon calculations, reproduces the experimental variable-temperatureTHz-Raman spectra and rules out the possibility of the phase transformations occurring via any classical soft mode. A combination of variable-temperature powder X-ray diffraction, solid-state NMR, and computational spectroscopy provides a detailed molecular description of the phase transitions, indicating a first-order diffusionless process between I → II and II → III, wherein both conformational changes and lattice distortions occur simultaneously in the crystal lattice. The study indicates that a nucleation and growth mechanism is compatible with concerted movements producing a conformational change in organic molecular crystals.