The results of the sixth blind test of organic crystal structure prediction methods are presented and discussed, highlighting progress for salts, hydrates and bulky flexible molecules, as well as on-going challenges.

We present a periodic density functional theory study of the stability of 350 organic cocrystals relative to their pure single-component structures, the largest study of cocrystals yet performed with high-level computational methods. Our calculations demonstrate that cocrystals are on average 8 kJ mol–1 more stable than their constituent single-component structures and are very rarely (<5% of cases) less stable; cocrystallization is almost always a thermodynamically favorable process. We consider the variation in stability between different categories of systems—hydrogen-bonded, halogen-bonded, and weakly bound cocrystals—finding that, contrary to chemical intuition, the presence of hydrogen or halogen bond interactions is not necessarily a good predictor of stability. Finally, we investigate the correlation of the relative stability with simple chemical descriptors: changes in packing efficiency and hydrogen bond strength. We find some broad qualitative agreement with chemical intuition—more densely packed cocrystals with stronger hydrogen bonding tend to be more stable—but the relationship is weak, suggesting that such simple descriptors do not capture the complex balance of interactions driving cocrystallization. Our conclusions suggest that while cocrystallization is often a thermodynamically favorable process, it remains difficult to formulate general rules to guide synthesis, highlighting the continued importance of high-level computation in predicting and rationalizing such systems.

We show how an embedded many-body expansion (EMBE) can be used to calculate accurate ab initio energies of water clusters and ice structures using wavefunction-based methods. We use the EMBE described recently by Bygrave et al. [J. Chem. Phys. 137, 164102 (2012)], in which the terms in the expansion are obtained from calculations on monomers, dimers, etc., acted on by an approximate representation of the embedding field due to all other molecules in the system, this field being a sum of Coulomb and exchange-repulsion fields. Our strategy is to separate the total energy of the system into Hartree-Fock and correlation parts, using the EMBE only for the correlation energy, with the Hartree-Fock energy calculated using standard molecular quantum chemistry for clusters and plane-wave methods for crystals. Our tests on a range of different water clusters up to the 16-mer show that for the second-order Møller-Plesset (MP2) method the EMBE truncated at 2-body level reproduces to better than 0.1 mE(h)/monomer the correlation energy from standard methods. The use of EMBE for computing coupled-cluster energies of clusters is also discussed. For the ice structures Ih, II, and VIII, we find that MP2 energies near the complete basis-set limit reproduce very well the experimental values of the absolute and relative binding energies, but that the use of coupled-cluster methods for many-body correlation (non-additive dispersion) is essential for a full description. Possible future applications of the EMBE approach are suggested.

Dispersion-corrected density-functional theory (DFT-D) methods have become the workhorse of many computational protocols for molecular crystal structure prediction due to their efficiency and convenience. However, certain limitations of DFT, such as delocalisation error, are often overlooked or are too expensive to remedy in solid-state applications. This error can lead to artificial stabilisation of charge-transfer and, in this work, it is found to affect the correct identification of the protonation site in multicomponent acid-base crystals. As such, commonly used DFT-D methods cannot be applied with any reliability to the study of acid-base co-crystals or salts, while hybrid functionals remain too restrictive for routine use. This presents an impetus for the development of new functionals with reduced delocalisation error for solid-state applications; the structures studied herein constitute an excellent benchmark for this purpose.The crystalline structures adopted by organic molecules often involve a compromise between many competing weak interactions. Thus, the area of crystal structure prediction (CSP) presents a stringent challenge for computational methods, where the relative energies between different packing arrangements must often be assessed to within accuracies of a few kJ mol −1 or less.[1] The goal of reliable CSP, which has potential applications in pharmaceutical solid-form screening[2] and the discovery of functional materials, [3,4] has demonstrated the effectiveness of solid-state density functional theory (DFT) for obtaining accurate structures and energetics of molecular crystals. The impressive success of dispersion-corrected DFT methods in CSP blind tests has led to increased use of these methods for modelling the organic molecular solid state.[1] However, a source of error that is not commonly acknowledged in this application area of DFT is delocalisation error.It has long been established that delocalisation error in local density functionals results in over-stabilisation of charge-transfer complexes and other species with separated charges. [5,6] This error is not seen in correlated-wavefunction theories and can be reduced for density-functional approximations (DFAs) through mixing of large amounts of exact (or Hartree-Fock, HF) exchange. Typically ca. 50% exact-exchange mixing is required to obtain accurate energetics for charge-transfer complexes, [7,8,9] charge-transfer excitation energies, [10,11,12] halogen-bonded complexes,[13] barrier heights of radical reactions, [14,15] and other cases where delocalisation error plagues local functionals.Several examples of density-driven delocalisation error have been noted, in which the improper density leads to significant errors in optimised geometries. This has been observed for the pre-reaction complex for H-atom abstraction from 1,4-diazabicyclo[2.2.2]octane (DABCO) by the benzyloxyl radical, where delocalisation error results in excessive stretching of one of the benzyloxyl C-H bonds.[16] Even more dramatic is the example of the carbani...

We combine state-of-the-art computational crystal structure prediction (CSP) techniques with a wide range of experimental crystallization methods to understand and explore crystal structure in pharmaceuticals and minimize the risk of unanticipated late-appearing polymorphs. Initially, we demonstrate the power of CSP to rationalize the difficulty in obtaining polymorphs of the well-known pharmaceutical isoniazid and show that CSP provides the structure of the recently obtained, but unsolved, Form III of this drug despite there being only a single resolved form for almost 70 years. More dramatically, our blind CSP study predicts a significant risk of polymorphism for the related iproniazid. Employing a wide variety of experimental techniques, including high-pressure experiments, we experimentally obtained the first three known nonsolvated crystal forms of iproniazid, all of which were successfully predicted in the CSP procedure. We demonstrate the power of CSP methods and free energy calculations to rationalize the observed elusiveness of the third form of iproniazid, the success of high-pressure experiments in obtaining it, and the ability of our synergistic computational-experimental approach to “de-risk” solid form landscapes.