Unravelling venetoclax solvate behaviour: insights from crystal structures and computational surface analysis

Seven venetoclax solvates were structurally characterized and studied for their desolvation behaviour, leading to the identification of two solvent-free polymorphs. Advanced crystallographic and computational analyses, including Solvate Analyser, CSD-Particle, FTIR and solid-state NMR, revealed key factors governing solvate stability and transformation. Notably, the acetone solvate exhibited exceptional stability and the desolvated forms retained the molecular arrangement of their parent solvates.

This study investigates venetoclax solvates and their nonsolvated forms through desolvation. Seven solvates were prepared and their structures solved from single-crystal X-ray diffraction data. Among these, two are cavity solvates while the remaining five are channel solvates, with three being isomorphous. De­solvation experiments led to two solvent-free crystalline polymorphs of venetoclax, forms A and B. Notably, the acetone solvate remained stable and did not convert to a nonsolvated form. Form B has a higher melting point and a faster intrinsic dissolution rate than form A. Advanced computational tools, including Solvate Analyser and CSD-Particle, provided insights into crystal surface properties and desolvation behaviour. Properties such as lattice energy, molecular interaction energy, attachment energy, surface rugosity and solvent arrangement within the crystal and on the surface were linked to solvate stability and subsequent transformation upon desolvation. A combination of FTIR, and ¹³C and ¹⁵N solid-state NMR spectroscopies showed that both short- and long-range molecular interactions and arrangements of venetoclax molecules in the desolvated forms closely resembled those in the parent solvates.