Facts and fictions about polymorphism.

Area of Science:

• Solid-state chemistry and materials science.
• Crystallography and computational chemistry.

Background:

• Polymorphism is crucial in pharmaceuticals and materials science, impacting properties and performance.
• Understanding factors influencing polymorphic behavior is essential for materials design.

Purpose of the Study:

• To investigate the prevalence and influencing factors of polymorphism using diverse datasets.
• To correlate molecular properties with the propensity for a compound to exhibit polymorphism.

Main Methods:

• Analysis of crystallographic data from the Cambridge Structural Database (CSD).
• Review of extensive solid-form screening data from pharmaceutical companies (Roche and Eli Lilly).
• Computation of crystal energies and properties using Density Functional Theory with dispersion correction (DFT-d) methods.

Main Results:

• No correlation found between molecular flexibility or size and polymorphism.
• Chiral molecules show a lower propensity for polymorphism compared to achiral ones.
• Hydrogen bonding slightly increases polymorphism propensity; energy differences between polymorphs are typically <1 kcal mol(-1), but conformational polymorphs can differ by up to 2.5 kcal mol(-1).
• Polymorphism prevalence: ~33% in CSD, ~50-75% in screened pharmaceutical compounds.

Conclusions:

• Polymorphism is a widespread phenomenon, particularly in industrially relevant compound sets.
• Predicting and controlling targeted polymorphism remains a significant challenge in materials science.
• While some factors (chirality) influence polymorphism, it is highly compound-specific.