Decoding Supramolecular Packing Patterns from Computed Anisotropic Deformability Maps of Molecular Crystals.

Area of Science:

• Solid-state chemistry
• Computational materials science
• Crystallography

Background:

• Engineering mechanical properties of active pharmaceutical ingredient (API) solid forms is crucial for drug development.
• Computational methods, specifically dispersion-corrected density functional theory (DFT), have advanced to enable reliable prediction of crystal mechanical responses.

Purpose of the Study:

• To establish structure-mechanics relations in molecular crystals using advanced computational methods.
• To demonstrate the capability of DFT in predicting and engineering the mechanical behavior of pharmaceutical solid forms.

Main Methods:

• Utilized many-body dispersion and Tkatchenko-Scheffler dispersion-corrected DFT to compute elastic constants.
• Calculated mechanical responses for archetypal systems including paracetamol, aspirin polymorphs, urea, and benzene crystals.

Main Results:

• Achieved semiquantitative and excellent qualitative agreement between computational predictions and experimental data.
• Revealed that the plane of maximal Young's modulus aligns with extended hydrogen-bond or π-π networks.
• Demonstrated that supramolecular packing programmably dictates mechanical behavior.

Conclusions:

• Structure-mechanics relations in molecular crystals can be reliably predicted using dispersion-corrected DFT.
• These findings provide a pathway to rationally design solid forms with enhanced physicochemical and compression properties for pharmaceutical applications.