Inconvenient Truths about Solid Form Landscapes Revealed in the Polymorphs and Hydrates of Gandotinib

Elucidating the structure relationships and transformation pathways of the solid forms of gandotinib was an enormous challenge. Only seven of the eleven experimentally observed forms crystallized directly from solution: a neat form (I), a tetrahydrate (Hy4), a 3.0-3.7-hydrate (HyY), and four solvates (methanol, n-propanol, n-butanol, and N-methyl-2-pyrrolidone). The four remaining forms (II, Hy2.2, Hy1.3, and HyX) were produced by dehydration and/or rehydration processes. Inter conversion of the anhydrates and hydrates of gandotinib with small changes in the relative humidity complicated identifying and characterizing the crystalline forms to such an extent that some experiments conducted in the humidity of summer could not be reproduced in the winter, and vice versa. Thus, with solid-state transformations being the only route to four of the solid forms, elucidating the crystal structural relationships underpinning the dehydration-rehydration pathways as a function of temperature and humidity required not only complementary experimental and computational methods, but also extreme patience. A key feature of this system is that the chlorofluorophenyl ring of gandotinib in the various neat and hydrated forms is disordered, but to different extents. Tetrahydrate Hy4 dehydrates to form II in a process that sees the disordered rings nearly completely reorder; rehydration of form II does not return Hy4 to the original, thermodynamic ratio of ring orientations, instead kinetically trapping the conformations in a disorder ratio close to that of form II. A crystal structure prediction of gandotinib showed that stable form I belongs to a large family of very similar low energy structures, all higher in lattice energy than the global minimum structure on the computed crystal energy landscape. By taking into account the contribution of disorder to the total free energy, form I is calculated to be energetically competitive with the global lattice energy minimum structure, suggesting that the thermodynamically most stable form has been found.