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.

Department of Chemical Engineering University of Chemistry and Technology Prague Technická 3 16628 Prague 6 Czechia

Department of Pharmaceutical Chemistry Poznan University of Medical Sciences 3 Rokietnicka 60 806 Poznań Poland

Faculty of Science Jan Evangelista Purkyně University in Ústí nad Labem Pasteurova 3632 15 400 96 Ústí nad Labem Czechia

Zentiva k s U Kabelovny 130 10237 Prague 10 Czechia

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