Predicting crystal form stability under real-world conditions.

Area of Science:

• Crystallography
• Computational Chemistry
• Materials Science

Background:

• Physicochemical properties of molecular crystals are critically dependent on their crystal form.
• In silico crystal form selection is advancing due to improved free-energy calculation methods.

Purpose of the Study:

• To enhance the accuracy of in silico free-energy calculations for crystal form selection.
• To establish a reliable experimental benchmark for solid-solid free-energy differences.
• To integrate hydrate and anhydrate crystal structures onto a unified energy landscape.

Main Methods:

• Improved accuracy in free-energy calculations.
• Development of an experimental benchmark for solid-solid free-energy differences.
• Quantification of statistical errors in computed free energies.
• Mapping of hydrate and anhydrate crystal structures on a temperature and relative humidity-dependent energy landscape.

Main Results:

• Achieved standard errors of 1-2 kJ/mol for free energies of industrially relevant compounds.
• Developed a method to place crystal structures with varying hydrate stoichiometries on the same energy landscape.
• Demonstrated applicability to multi-component systems, including solvates.

Conclusions:

• The enhanced computational approach significantly reduces the gap between experimental needs and computational capabilities.
• Crystal structure prediction is transformed into a more reliable and actionable procedure.
• This method aids in directing crystal form selection and establishing control in materials science and drug development.