Are high-Z' polymorphs metastable? Insight from pharmaceutical polymorphs

Area of Science:

• Crystallography
• Solid-state chemistry
• Computational chemistry

Background:

• High-Z' polymorphs are theorized to be less stable than low-Z' forms.
• This symmetry-stability relationship lacks experimental or computational validation.
• Analyzing high-Z' structures is computationally challenging due to large atom counts.

Purpose of the Study:

• To computationally assess the relationship between Z' and stability in drug polymorphs.
• To determine if crystal structures with more molecules per asymmetric unit are inherently less stable.
• To provide evidence for or against the fundamental hypothesis of symmetry-driven stability in molecular crystals.

Main Methods:

• Utilized the CE-B3LYP method for efficient Lattice Cohesive Energy (LCE) estimation.
• Analyzed 49 polymorphs across 15 different drugs.
• Evaluated LCEs, Kitaigorodskii packing indices (KPI), molecular volumes, and crystal densities.

Main Results:

• No direct correlation was found between Z' (number of molecules in the asymmetric unit) and polymorph stability.
• Lattice cohesive energies did not consistently decrease with increasing Z'.
• Kitaigorodskii packing indices, molecular volumes, and crystal densities also showed no clear trend with Z'.

Conclusions:

• The hypothesis that high-Z' polymorphs are inherently less stable is not supported by this study.
• Crystal stability in drug polymorphs is not directly dictated by the number of molecules in the asymmetric unit.
• Further research may be needed to identify other factors governing polymorph stability.