Observation of oscillatory behavior during the dissolution of a pharmaceutical compound and evidence for the existence of an inverse Ostwald rule

Abstract

Oscillatory kinetic behavior is reported for the first time in a solid-state phase transformation of an organic compound, specifically, in the dissolution of Form V crystals of etoricoxib in neat toluene. The dissolution involves kinetics of bistability due to the generation of a second polymorph, Form I, during the process. While an attempt is made to reconcile the periodic behavior with the oscillatory rate coefficient predicted by time-dependent Marcus theory, more successful simulations of the data are obtained using superimposed, elementary dispersive kinetic models for both dissolution and nucleation-and-growth. Contrastingly, the dissolution of Form V in toluene containing a suspected small quantity of methanol/base contaminant shows that the phase transformation of Form V to the less-stable Form I crystals is rate-limiting and that the process is well described by a single, elementary dispersive kinetic model (i.e., no oscillations are observed). The latter observation lends support to the bistability hypothesis and provides evidence for the existence of a “corollary” to Ostwald's rule of stages.