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 11 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. Interconversion 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 co...