Predicting crystal form stability under real-world conditions

Dzmitry Firaha (), Yifei Michelle Liu (), Jacco Streek, Kiran Sasikumar, Hanno Dietrich, Julian Helfferich, Luc Aerts, Doris E. Braun, Anders Broo, Antonio G. DiPasquale, Alfred Y. Lee, Sarah Meur, Sten O. Nilsson Lill, Walter J. Lunsmann, Alessandra Mattei, Pierandrea Muglia, Okky Dwichandra Putra, Mohamed Raoui, Susan M. Reutzel-Edens, Sandrine Rome, Ahmad Y. Sheikh, Alexandre Tkatchenko, Grahame R. Woollam and Marcus A. Neumann ()
Additional contact information
Dzmitry Firaha: Avant-garde Materials Simulation
Yifei Michelle Liu: Avant-garde Materials Simulation
Jacco Streek: Avant-garde Materials Simulation
Kiran Sasikumar: Avant-garde Materials Simulation
Hanno Dietrich: Avant-garde Materials Simulation
Julian Helfferich: Avant-garde Materials Simulation
Luc Aerts: Chemin du Foriest
Doris E. Braun: University of Innsbruck
Anders Broo: AstraZeneca Gothenburg
Antonio G. DiPasquale: Genentech
Alfred Y. Lee: Analytical Research & Development
Sarah Meur: Chemin du Foriest
Sten O. Nilsson Lill: AstraZeneca Gothenburg
Walter J. Lunsmann: GRIN Therapeutics
Alessandra Mattei: AbbVie
Pierandrea Muglia: GRIN Therapeutics
Okky Dwichandra Putra: AstraZeneca Gothenburg
Mohamed Raoui: Novartis Pharma
Susan M. Reutzel-Edens: Cambridge Crystallographic Data Centre
Sandrine Rome: Chemin du Foriest
Ahmad Y. Sheikh: AbbVie
Alexandre Tkatchenko: University of Luxembourg
Grahame R. Woollam: Novartis Pharma
Marcus A. Neumann: Avant-garde Materials Simulation

Nature, 2023, vol. 623, issue 7986, 324-328

Abstract: Abstract The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations2–4. 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 control5.

Date: 2023
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DOI: 10.1038/s41586-023-06587-3

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