Predicting crystal form stability under real-world conditions

Predicting crystal form stability under real-world conditions

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form 1 . In silico crystal form selection has recently come much closer to realization because of the development of accurate and afford...

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Published in:Nature (London) Vol. 623; no. 7986; pp. 324 - 328
Main Authors: Firaha, Dzmitry, Liu, Yifei Michelle, van de Streek, Jacco, Sasikumar, Kiran, Dietrich, Hanno, Helfferich, Julian, Aerts, Luc, Braun, Doris E., Broo, Anders, DiPasquale, Antonio G., Lee, Alfred Y., Le Meur, Sarah, Nilsson Lill, Sten O., Lunsmann, Walter J., Mattei, Alessandra, Muglia, Pierandrea, Putra, Okky Dwichandra, Raoui, Mohamed, Reutzel-Edens, Susan M., Rome, Sandrine, Sheikh, Ahmad Y., Tkatchenko, Alexandre, Woollam, Grahame R., Neumann, Marcus A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 09-11-2023
Nature Publishing Group
Subjects:
119/118
639/301/1034/1037
639/638/298
639/638/309/2144
Accuracy
Bioavailability
Crystal structure
Crystals
Energy
Errors
Free energy
Humanities and Social Sciences
Humidity
Mathematical analysis
multidisciplinary
Phase transitions
Physicochemical properties
Relative humidity
Risk assessment
Science
Science (multidisciplinary)
Software
Solubility
Stability
Standard deviation
Stoichiometry
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Description
Summary:The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form 1 . In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations 2 – 4 . Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1–2 kJ mol −1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control 5 . Accuracy of free-energy calculations can be improved by constructing an experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate and anhydrate crystal structures on the same energy landscape.
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ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-023-06587-3