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

Area of Science:

• Solid-state chemistry
• Crystallography
• Pharmaceutical science

Background:

• Venetoclax is a crucial medication, and understanding its solid-state forms is vital for drug development.
• Solvates, crystalline forms containing solvent molecules, significantly impact drug properties.
• Investigating desolvation pathways reveals insights into crystal stability and polymorphism.

Purpose of the Study:

• To characterize seven venetoclax solvates and their corresponding solvent-free forms.
• To elucidate the structural and energetic factors governing solvate stability and desolvation.
• To evaluate the physicochemical properties of the resulting crystalline polymorphs.

Main Methods:

• Single-crystal X-ray diffraction for structural determination.
• Desolvation experiments under controlled conditions.
• Solid-state spectroscopy (FTIR, 13C and 15N NMR).
• Computational modeling (Solvate Analyser, CSD-Particle).

Main Results:

• Seven venetoclax solvates were prepared, classified as cavity or channel types.
• Two solvent-free crystalline polymorphs, forms A and B, were obtained via desolvation.
• Form B exhibited a higher melting point and faster intrinsic dissolution rate compared to Form A.
• The acetone solvate demonstrated remarkable stability, resisting desolvation.
• Computational analysis linked crystal properties to solvate stability and desolvation behavior.

Conclusions:

• Desolvation of venetoclax solvates yields distinct crystalline polymorphs with varying properties.
• Crystal surface properties and molecular interactions are key determinants of solvate stability.
• Understanding these solid-state transformations is critical for optimizing venetoclax formulation and delivery.