Kinetics of Solid-State Phase Transformations Governed by Nuclei

Nucleation is a ubiquitous process in nature. Nucleation and its complementary process, denucleation, are involved in a variety of pharmaceutically relevant phenomena that can affect both the manufacture and performance of developmental drug candidates. Likewise, those same mechanisms can be expected to impact nanoformulations as it is easy to envision a natural link between nuclei and nanoparticles via their size. While (de-)nucleation kinetics have remained poorly understood to the present time, that understanding can be critical for prediction and, ultimately, control of key physicochemical and biorelevant properties of nanoparticles composed of a given drug substance. In this talk, the use of dispersive kinetic models (DKMs) for describing various nucleation and denucleation rate-limited phase transformations will be discussed in the context of several real-world examples. The use of DKMs to predict activation energy distributions and nuclei particle size distributions will also be presented. Lastly, a currently marketed (by Merck/MSD) nanoformulation will be discussed to highlight an important in vivo advantage of nanosized particles of a drug substance in overcoming a dramatic food effect.