The role of solvent diffusion on the thermal desolvation and polymorphic transformation of a pharmaceutical solvate: experimental kinetics and multiscale modelling

In drug manufacturing, when solvent-based methods are used for the crystallization of active pharmaceutical ingredients (APIs), often, the solvent can weakly interact with the API resulting in the formation of a new solid form, the so-called solvate. Thus, when desolvation occurs upon heating it can result in either a known stable form or the recrystallization to a new solid form. In this work, we researched the desolvation kinetics of the fluorobenzene (FB) solvates of Ibrutinib (IBR) by combining thermogravimetric analysis (TGA), in-situ powder X-ray diffraction (PXRD), all-atom molecular dynamics (MD) simulations, and macroscopic modelling of the desolvation kinetics. Using model-fitting and iso-conversional methods, we accurately predicted the desolvation kinetics by validating both TGA and XRPD data as well as calculated the activation energy of desolvation. Performing a large set of MD simulations, we traced individual FB molecules and then calculated the activation energy for their diffusion. Our results show that the desolvation kinetics is rather affected by the diffusion of FB in the crystal lattice than by polymorphic transformations.