Unraveling the solid-state complexity of pirtobrutinib: Polymorphs, solvates, hydrates, and their transformation pathways

• Expanded solid-state landscape of pirtobrutinib: seven novel solid forms identified. • Intermediate solvate as key precursor enabling access to alternative solid forms. • Desolvation pathway used to obtain specific polymorph. • Impurity-driven crystallization leading to polymorph formation. • Chiral compound with pseudoinversion centers observed. A comprehensive solid-state screening of pirtobrutinib led to the identification of five anhydrates ( I - V ), five solvates, two hydrates ( Hy1, HyA ), and the amorphous phase. Extensive structural and thermal characterization was performed using hot-stage microscopy, thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy, and both powder and single-crystal X-ray diffraction. The crystal structures of two anhydrates ( I and III ) were solved, both crystallizing with two molecules in the asymmetric unit and exhibiting pseudosymmetry. In addition, unit cell and space group information were obtained for several other forms. Three solvates were identified as isostructural, one as unstable, and a fifth as a solvate polymorph. Form V was not directly obtained by crystallization but was only accessible through desolvation. Hy1 was identified as a stoichiometric monohydrate, whereas HyA exhibits non-stoichiometric hydration behavior. Structural similarities between Hy1 and the methanol solvate, as well as between HyA and Form V , suggest that the formation of these hydrates depends on specific precursor structures. Form I emerged as the most frequently obtained and a stable polymorph, crystallizing under a broad range of experimental conditions. It was found to be monotropically related to Forms II and V , and enantiotropically related to Forms III and IV . The formation of the latter two forms was linked to the presence of an unidentified impurity. This study highlights the importance of comprehensive solid-form screening, particularly with regard to solvates (hydrates) and the amorphous form, for understanding solid-state transformation pathways, desolvation behavior, and for enabling form selection in pharmaceutical development.