Abstract
Crystal structure prediction is based on the assumption that the most thermodynamically stable structure will crystallize first. The existence of other structures such as polymorphs or from counterenantiomers requires an accurate calculation of the electronic energy. Using atom-centered Gaussian basis functions in periodic Density Functional Theory (DFT) calculations in Turbomole, the performance of two dispersion-corrected functionals, PBE-D3 and B97-D, is assessed for molecular organic crystals of the X23 benchmark set. B97-D shows a MAE (mean absolute error) of 4 kJ/mol, compared to 9 kJ/mol for PBE-D3. A strategy for the convergence of lattice energies towards the basis set limit is outlined. A simultaneous minimization of molecular structures and lattice parameters shows that both methods are able to reproduce experimental unit cell parameters to within 4–5%. Calculated lattice energies, however, deviate slightly more from the experiment, i.e., by 0.4 kJ/mol after unit cell optimization for PBE-D3 and 0.5 kJ/mol for B97-D. The accuracy of the calculated lattice energies compared to the experimental values demonstrates the ability of current DFT methods to assist in the quest for possible polymorphs and enantioselective crystallization processes.
Highlights
The determination and accurate calculation of the relative energies of even small molecular crystals is a challenge, both experimentally and theoretically
Administration (FDA) guidelines require new chiral drugs to be marked as single enantiomers for which a full control of the stereoselectivity must be guaranteed at every stage of the production process, or the absence of side effects for the other stereoisomer must be demonstrated [1,2,3]
The lattice energy differences between different polymorphs are usually below 4 kJ/mol−1 [6], which is in the same range as the differences in lattice energy between enantiopure and racemic crystals [7,8]
Summary
The determination and accurate calculation of the relative energies of even small molecular crystals is a challenge, both experimentally and theoretically. Administration (FDA) guidelines require new chiral drugs to be marked as single enantiomers for which a full control of the stereoselectivity must be guaranteed at every stage of the production process, or the absence of side effects for the other stereoisomer must be demonstrated [1,2,3]. It is not clear whether the crystallisation of pharmaceutical molecules is controlled by thermodynamics or kinetics [4]. The lattice energy differences between different polymorphs are usually below 4 kJ/mol−1 (in 80% of the cases) [6], which is in the same range as the differences in lattice energy between enantiopure and racemic crystals [7,8]
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