Different thermal and solubility properties with an identical crystal structure – case of lenalidomide hydrate†

Identification of the polymorphism of a medicine is critical for its pharmaceutical properties. Different thermal properties and solubilities indicate different polymorphs. However, in the case of lenalidomide (LDM) hydrate, crystals with different thermal and solubility properties were determined to have an identical crystal structure. LDM, a drug for multiple myeloma and myelodysplastic syndrome, was found to form two dihydrate crystals. The stick-shaped crystals, E1, exhibit a two-step dehydration process, while the rhombic prism-shaped crystals, E2, show a one-step rapid dehydration process. E1 and E2 also showed different dissolution rates. However, powder XRD patterns of E1 and E2 were identical, and their crystal structures were confirmed as identical by single-crystal XRD. Further, investigation into the arrangement of water molecules showed that E1 and E2 contained features of both channel and isolated site hydrates. Water channels parallel to the c-axis were discovered in the hydrated structure, and two dehydration mechanisms were proposed based on the grinding experiments and lattice orientation analysis. E1 and E2 were mainly dehydrated along and perpendicular to the water channels, respectively. In addition, dehydration kinetics and the solid-phase transformation of E1 and E2 were determined.