Luca
Iuzzolino
a,
Patrick
McCabe
b,
Sarah L.
Price
a and
Jan Gerit
Brandenburg‡
*a
aDepartment of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK. E-mail: gerit.brandenburg@chemie.uni-goettingen.de
bThe Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK
First published on 27th February 2018
Successful methodologies for theoretical crystal structure prediction (CSP) on flexible pharmaceutical-like organic molecules explore the lattice energy surface to find a set of plausible crystal structures. The initial search stages of CSP studies use relatively simple lattice energy approximations as hundreds of thousands of minima have to be considered. These generated crystal structures often have poor molecular geometries, as well as inaccurate lattice energy rankings, and performing reasonably accurate but computationally affordable optimisations of the crystal structures generated in a search would be highly desirable. Here, we seek to explore whether semi-empirical quantum-mechanical methods can perform this task. We employed the dispersion-corrected tight-binding Hamiltonian (DFTB3-D3) to relax all the inter- and intra-molecular degrees of freedom of several thousands of generated crystal structures of five pharmaceutical-like molecules, saving a large amount of computational effort compared to earlier studies. The computational cost scales better with molecular size and flexibility than other CSP methods, suggesting that it could be extended to even larger and more flexible molecules. On average, this optimisation improved the average reproduction of the eight experimental crystal structures (RMSD15) and experimental conformers (RMSD1) by 4% and 23%, respectively. The intermolecular interactions were then further optimised using distributed multipoles, derived from the molecular wave-functions, to accurately describe the electrostatic components of the intermolecular energies. In all cases, the experimental crystal structures are close to the top of the lattice energy ranking. Phonon calculations on some of the lowest energy structures were also performed with DFTB3-D3 methods to calculate the vibrational component of the Helmholtz free energy, providing further insights into the solid-state behaviour of the target molecules. We conclude that DFTB3-D3 is a cost-effective method for optimising flexible molecules, bridging the gap between the approximate methods used in CSP searches for generating crystal structures and more accurate methods required in the final energy ranking.
All CSP methods begin with a search step in which the lattice energy (Elatt) surface is explored to locate all the possible local minima, each corresponding to a separate possible crystal structure.1,29 Since the surface that must be explored is extremely wide, especially for flexible molecules, a large number of candidate crystal structures are produced, at least of the order of hundreds of thousands.22,29 Hence, cheaper but less accurate energy models must be utilised in the search. They can take the form of tailor-made force fields,30 exp-6 atomistic intermolecular potentials combined with quantum-mechanical calculations of the conformational energy,31,32 or transferrable empirical force fields.33
The lattice energy evaluations used in the crystal structure generation (“search”) stage are rarely accurate enough to give a reliable energy ranking, since the lattice energy differences between observed polymorphs are usually less than 5 kJ mol−1. Hence, thousands of generated crystal structures must be optimised and re-ranked to obtain a meaningful list of PPMs. Since this final step requires the use of accurate and expensive models, such as periodic dispersion-corrected density functional theory (DFT-D)34–40 on all crystal structures (the Ψcrys method), or the calculation of a high-quality wave-function for each molecular conformer (the Ψmol method),8,41,42 the computational cost can easily become unfeasible. A possible solution is the use of an intermediate optimisation method, which can bridge the gap between the simple models used to generate the crystal structures and the more accurate ones used to generate an accurate final energy ranking. For flexible molecules, several intermediate methods are used in different CSP workflows, such as optimising some torsion angles with a transferable force-field to improve the molecular conformation geometries,43,44 single-point energy calculations with a more accurate description of the intra- and intermolecular interactions18,20 or partial lattice energy optimisations.1,22
Recently, semi-empirical QM methods have been applied to large chemical and biochemical systems;45,46 these methods do not have the transferability problems of standard force fields but are significantly less demanding than other QM methods.45,47,48 In this work, the interest is focused on dispersion-corrected density functional tight binding methods (DFTB3-D3), which are up to three orders of magnitude cheaper than DFT-D, and have been shown to provide reasonably accurate lattice energies for a benchmark of small molecular crystals.49 We present the first use of semi-empirical QM methods within a full CSP workflow. We aim to verify whether DFTB3-D3 can be used as an intermediate re-ranking step in CSP. There are at least four ways in which it could provide useful insights:
(1) Producing more accurate molecular and crystalline geometries and packings than the original crystal structures generated in the search, which could be used as starting points for better lattice energy evaluations.
(2) Obtaining a more accurate energy ranking than the one obtained after the crystal structure search, in order to limit the number of structures that need to be taken to the final optimisation stage.
(3) Producing fewer minima that are artefacts of the constraints imposed by the space group and conformational variables, by optimising all crystal structures with P1 symmetry.
(4) Computing the phonon modes of plausible crystal structures to estimate thermodynamic free energies in the harmonic approximation.
We test the suitability of DFTB3-D3 for these purposes on structures generated in a set of searches25 performed with the Ψmol method. Elatt, the energy needed to completely separate all the molecules in the static crystal structure to isolated molecules in their most stable conformation,10 can be described as:
Elatt = Uinter + ΔEintra |
ΔEintra is the energy penalty for modifying the conformation of the molecule from its isolated gas-phase minimum, calculated with a good quality molecular electronic structure method, and Uinter is the intermolecular energy, which sums all the interactions between the molecules in the crystal.10 The search method variant used in this work treated the most flexible torsion angles as search variables, and the other conformational degrees of freedom correspond to the isolated molecule ab initio values, an approach that is comparable to using multiple rigid conformations.43 Five flexible molecules for which full CSP studies had already been performed (Fig. 1) are used to test the application of DFTB3-D3 methods: molecule XX was the first “pharmaceutical-like” molecule used in a Blind Test,50 XXIII and XXVI are from the sixth blind test,1 GSK269984B was used in an early pharmaceutical study,23 while the CSP study of mebendazole was performed for an on-going collaboration.51 These CSP methods were successful in predicting all the observed polymorphs with one molecule in the asymmetric unit cell (i.e. Z′ = 1), and so provide a stringent test for the suitability of an intermediate DFTB3-D3 step to extend CSP methods to even larger, more flexible molecules.
Structure relaxations have been conducted with a quasi-Newton optimisation in internal redundant coordinates as implemented in the CRYSTAL14 programme.74 As DFTB3-D3 is used as an intermediate optimisation method, it is important to test the relaxation thresholds. This was tested on the POLY59 benchmark set75 and an optimum trade-off between the accuracy in relative energy ranking and computational cost was obtained with thresholds of 0.12 a.u. and 0.003 a.u. for the root-mean-square (RMS) displacement and RMS gradient.
Phonon calculations were used as a final step to estimate the free energies for the experimental crystal structures and a few diverse low energy structures (given in ESI Table 10†). Phonon calculations using symmetric finite displacements required geometry optimisations with one order of magnitude tighter thresholds, corresponding to the default settings in CRYSTAL14. The Brillouin zone sampling for the phonon calculations was initially formed by the common practice of constructing supercells with minimum cell lengths of 10 Å.70 As we are interested in relative polymorph energies, we additionally ensured that a similar number of atoms are covered in each supercell to enhance possible error compensations. The Helmholtz free energy, A, can be defined as:
A = Elatt + Fvib |
The energy ranking calculated via DFTB3-D3 proved to be very different, as shown in Fig. 2 for XXVI, with the calculated Elatt values having a larger energy spread than after the search stage. However, the poor energies of the structures corresponding to the experimental forms showed that, contrary to the original hope, DFTB3-D3 had not produced a more accurate energy ranking. Hence, all the unique optimised crystal structures within a large window of 50 kJ mol−1 of the global minimum in DFTB3-D3 energy were taken forward. Clustering to remove duplicates and applying the energy cut-off each reduced the number of structures by a molecule-dependent proportion, which is broken down in ESI Table 1.† This resulted in 3346 crystal structures for molecule XXVI, 5328 for GSK269984B, 13490 for molecule XXIII, 19146 for molecule XX, 3078 for the A tautomer of mebendazole and 3352 for its C tautomer, requiring optimisation with a more accurate method.
Fig. 2 The energy distributions of the computer-generated crystal structures of molecule XXVI showing how the ∼9000 structures below 40 kJ mol−1 generated by the CrystalPredictor search (blue) are optimised by DFTB3-D3 (orange) to provide only ∼3000 structures below 50 kJ mol−1, and their corresponding energies calculated by DMACRYS using the ΨPBE0+FITmol model (black). The coloured circles indicate the energies of the experimental structures relative to the global minimum in Elatt at that stage. Similar plots for the other molecules are shown in ESI Fig. 1–5.† |
Rigid-molecule harmonic phonon calculations were carried out on the same structures as for the DFTB3-D3 phonons with DMACRYS using supercells generated following the methodology of Nyman and Day.80 This computationally cheap approach effectively assumes that the molecular modes do not affect ΔFvib, in contrast to the DFTB3-D3 calculations that allow the molecular and lattice modes to couple. The rigid-molecule ΨPBE0+FITmol model assumes that the molecular modes make an identical contribution to Fvib for all structures. This is a necessary assumption since the pure molecular modes could only be calculated at a local isolated-molecule minimum, and many conformations are far from such minima (although they would not necessarily be defined as conformational polymorphs).81
The generated crystal structures that upon optimisation ended up matching the experimental crystal structures and the significant computer-generated PPMs25 were optimised with CrystalOptimizer82 at the PBE0 6-31G(d,p) level of theory, as a function of a set of torsion and bond angles (shown in ESI Fig. 6†) that were selected according to rules defined by Nyman and Day26 based on chemical intuition derived from small model molecules. These calculations were used as a stringent test to verify how the geometries and energies obtained using DFTB3-D3 and ΨPBE0+FITmol compare with those obtained through optimising the most flexible conformational degrees of freedom using a more accurate and computationally expensive Ψmol model.
Experimental crystal structure (CSD refcode) | Reproduction of the experimental conformers (RMSD1) | Reproduction of the experimental crystal lattices (RMSD15) | |||||
---|---|---|---|---|---|---|---|
Search/Å | DFTB3-D3/Å | CrystalOptimizer/Å | Search/Å | DFTB3-D3/Å | ΨPBE0+FITmol/Å | CrystalOptimizer/Å | |
XXVI (XAFQIH) | 0.2 | 0.133 | 0.123 | 0.533 | 0.425 | 0.376 | 0.294 |
GSK269984B (BIFHOP) | 0.093 | 0.071 | 0.094 | 0.219 | 0.329 | 0.212 | 0.21 |
XXIII a (XAFPAY) | 0.236 | 0.216 | 0.212 | 0.689 | 0.68 | 0.663 | 0.443 |
XXIII b (XAFPAY01) | 0.278 | 0.18 | 0.159 | 0.626 | 0.528 | 0.415 | 0.373 |
XXIII d (XAFPAY03) | 0.31 | 0.278 | 0.237 | 0.511 | 0.544 | 0.583 | 0.53 |
XX (OBEQIX) | 0.227 | 0.137 | 0.101 | 0.455 | 0.469 | 0.39 | 0.218 |
Mebendazole A (TUXPEJ) | 0.201 | 0.176 | 0.143 | 0.465 | 0.408 | 0.402 | 0.321 |
Mebendazole C (YULGIW) | 0.096 | 0.067 | 0.066 | 0.825 | 0.763 | 0.313 | 0.28 |
Average | 0.205 | 0.157 | 0.142 | 0.540 | 0.518 | 0.419 | 0.334 |
Standard deviation | 0.073 | 0.067 | 0.055 | 0.169 | 0.135 | 0.134 | 0.103 |
DFTB3-D3 optimisations are effective at improving all the crystalline molecular conformations from the search generated structure, with a 23% improvement in the average RMSD1. The improvement in the overall crystal packing is more variable, with some becoming slightly worse and some slightly better with a mere 4% improvement in the average RMSD15. Keeping the molecule rigid at the DFTB3-D3 geometry but using the distributed multipoles and intramolecular energy from a superior electronic structure method improves the intermolecular packing, leading to an overall improvement of the average RMSD15 of 22% after the ΨPBE0+FITmol optimisations. Both the molecular and crystalline geometries are of a slightly worse quality than those obtained after the CrystalOptimizer optimisations, which improve the search structure by an average RMSD1 of 31% and an average RMSD15 of 38%. However, DFTB3-D3 refinements could be carried out at a much lower computational cost for these types of molecules, and yet successfully reproduced the structures.
Experimental crystal structure | Ranking after search | ΔElatt after search/kJ mol−1 | Ranking after DFTB3-D3 | ΔElatt after DFTB3-D3/kJ mol−1 | Ranking after ΨPBE0+FITmol | ΔElatt after ΨPBE0+FITmol/kJ mol−1 | Ranking in previous CSP study | ΔElatt in previous CSP study/kJ mol−1 |
---|---|---|---|---|---|---|---|---|
a The crystal structures of the two tautomers of mebendazole are ranked together. | ||||||||
XXVI (XAFQIH) | 262 | 20.5 | 208 | 25.44 | 2 | 1.96 | 2 | 0.49 |
GSK269984B (BIFHOP) | 54 | 6.63 | 1803 | 37.2 | 1 | 0 | 1 | 0 |
XXIII a (XAFPAY) | 4311 | 20.57 | 3670 | 33.8 | 232 | 12.31 | 280 | 13.52 |
XXIII B (XAFPAY01) | 55 | 7.72 | 805 | 23.49 | 3 | 0.82 | 1 | 0 |
XXIII D (XAFPAY03) | 1318 | 16.28 | 3748 | 33.99 | 114 | 10.25 | 85 | 9.21 |
XX (OBEQIX) | 10 | 3.86 | 10 | 2.94 | 1 | 0 | 1 | 0 |
Mebendazole A (TUXPEJ)a | 2 | 1.37 | 14 | 4.32 | 1 | 0 | 1 | 0 |
Mebendazole C (YULGIW)a | 92 | 9.64 | 101 | 8.96 | 15 | 5.78 | 4 | 2.55 |
DFTB3-D3 energies are inadequate for CSP and in most cases the experimental crystal structures are ranked worse than after the search. On the other hand, the final optimisation of just Uinter (i.e. keeping the DFTB3-D3-optimised molecular geometries rigid) with the ΨPBE0+FITmol model leads to a large improvement in the relative energies, with the crystal structures matching their experimental counterparts having rankings similar to those in the original CSP studies, which had been performed at a much larger computational cost. In three cases (molecule XX, GSK269984B, and mebendazole form A) the experimental crystal structure is still the global minimum. Experimental form B of molecule XXIII, form C of mebendazole, and XXVI are all within a few kJ mol−1 of the global minimum, while forms A and D of molecule XXIII are higher in energy, although still within a sensible energy window considering the issues with predicting the stability of the polymorphs of XXIII with any method as shown in Fig. 5.1
A question that arises is whether the energy landscapes, such as the two examples in Fig. 3, differ significantly in the range of putative polymorphs produced. Any comparison with the original studies is not straightforward because of the developments in the algorithms, variations in settings and the potential energy surfaces being used. A selection of the lowest energy PPMs and a few conformationally diverse structures from the original CSP studies had been selected for testing the workflow for generating the crystal structures25 and we find that the vast majority of these structures remain (see ESI Tables 3–7†) on the crystal energy landscapes (Fig. 3 and ESI Fig. 7–9†). Out of the 180 targeted PPMs for the five molecules, 21 were not found in the set of ΨPBE0+FITmol optimised crystal structures. However, in eight of those cases the PPMs were already missing after the search, and for a further nine the recent search structure was a very poor match.25 Only four PPMs that had been considered as ‘certainly found’ in the search25 were lost in this study, and either these were towards the high energy end of the sample, or similar types of packing are present in the crystal energy landscape. Some PPMs were found, but only above 20 kJ mol−1 from the global minimum. This can reflect the huge sensitivity of Elatt to quite subtle changes in conformation, particularly when hydrogen bonds can be inter- or intramolecular as in GSK269984B, and a crystal structure containing a molecular conformation optimised at the DFTB3-D3 level may converge to a less favourable local minimum when the intermolecular interactions are optimised with the ΨPBE0+FITmol method. The huge dependence of Elatt on subtle changes is further highlighted by the differences between the energies obtained in previous CSP studies and those obtained via re-optimisation of the key crystal structures with CrystalOptimizer, as shown in ESI Tables 3–7.† These optimisations also seem to lead to different geometries compared to the ΨPBE0+FITmol optimised crystal structures, highlighting how different routes can lead to different outcomes.
Fig. 3 Crystal energy landscapes of molecules (left) XX and (right) XXIII, with Elatt calculated by ΨPBE0+FITmol, plotted against the density of each crystal structure. The structures corresponding to the three experimental forms with Z′ = 1 only are given, with the relative energies of the Z′ = 2 polymorphs of XXIII being shown in Fig. 5. |
Fig. 4 The relative vibrational contributions to the Helmholtz free energy ΔFvib, which can be added to Elatt to calculate A. For each molecule, ΔFvib is calculated relative to the structure which is the Elatt global minimum within the ΨPBE0+FITmol method, for which ΔFvib = 0. The experimental structures are in green. The rigid-body modes are pure lattice modes, calculated from the Ψmol method. Full details about the crystal structures and their energies at the different stages can be found in ESI Table 10.† |
It is clear that the inclusion of the coupling of the molecular modes with the lattice modes in the DFTB3-D3 calculations leads to a wider range of free energy differences than with rigid-body phonons, implying that there is a considerable effect from the variations of the modes in different conformations and their couplings. The rigid-body phonons, which used 4 or 5 linear supercells to converge the Brillouin zone sampling, may be subject to greater errors in ignoring the coupling of the modes for this type of molecule.
The numerical results shown in Table 2 suggest that DFTB3-D3 is of similar accuracy to PBE0 partial optimisation using CrystalOptimizer for reproducing the experimental conformers, as judged by RMSD1 values. Holding the DFTB3-D3 conformations as rigid during the final optimisation with the ΨPBE0+FITmol model gives a slightly worse reproduction of the crystal structures in terms of RMSD15, but at a reduced cost. Comparisons with the experimental conformations (see ESI Table 2†) show that in most cases the DFTB3-D3 reproduction is good, probably within the amplitude of the vibrational motions of the terminal groups. The only exception is XXIII form D, where the optimisations have found a conformer close to the search generated structure, but visually different from the experimental one. The differences between crystal structures, as judged by RMSD15, powder pattern similarity, or any other measure, raise the issue of clustering: how can one eliminate duplicates while being certain not to eliminate potential polymorphs? Many polymorphs are very similar in their packing.84 Determining which structures correspond to distinct free energy minima at crystallisation temperatures requires realistic and expensive modelling of molecular motions within the crystals and would only ever be applied to the most promising PPMs resulting from a CSP study. The question of whether structures could remain distinct during crystallisation and growth is closely linked to the possibility of disorder within crystal structures, and indeed CSP can help rationalise disordered pharmaceuticals.8,11 For example, molecules that can pack in hydrogen-bonded layers that can stack in different ways with similar energies could form polytypic packings or have stacking faults.20 Closely related structures can manifest as static or dynamic disorder depending on the energy barriers.17 Hence, decisions about the extent of the search and the clustering criteria can have a major effect on the number of structures that need to be considered and their interpretation. It appears that using an electronic structure level optimisation (DFTB3-D3) has not significantly reduced the number of minima (only by 1–4%, see ESI Table 1†) for the molecules considered in this study, hinting that few structures are artefacts of the Ψmol approach.
The disappointment is that the relative energies generated by DFTB3-D3 are too poor (see ESI Section 2.3.1†) to allow a confident, drastic reduction in the number of structures to be investigated with more accurate and expensive methods. This is probably due to the limitations of this methodology, such as the approximate Hamiltonian used in the molecular overlap regime where atoms are in van der Waals contact, and approximating the long-range electrostatic potential by atomic monopoles, although they are iterated to self-consistency to allow some polarisation of the molecules by the field of the other molecules.59 There is also an underestimation of the Pauli repulsion that can lead to an overestimate of the density of molecular crystals;45 the unbalanced description of Pauli repulsion in the parametrization of DFTB seems to originate from the underlying basis confinement.60 Some observed deficiencies in hydrogen bond and halogen bond geometries and energies have led to the proposal of additional corrections,71,73 but these do not seem to improve the results for large molecular assemblies.46 The long range electrostatic interactions are described by atomic charges in both DFTB3-D3 and in the crystal generation stage, but from atomic multipoles in the final energy evaluation, and the quality of the electrostatic model is very critical in crystal structure prediction, particularly for polar hydrogen bonded molecules;85 this explains why the final energy ranking appears to be much more accurate than the initial and intermediate ones. Several other differences between the various methodologies employed exist in the ways in which intra- and intermolecular interactions are treated and how they are combined to optimise the crystal structures and calculate Elatt. All these differences play a part in determining the quality of the geometries and of the energy ranking, and it appears that despite the clear advantages of periodic electronic methods a high-quality crystal energy landscape cannot be calculated with a simplified wave-function.
DFTB3-D3 and the Ψmol approach are less applicable in the presence of strong induction forces, suggesting they should not be used for salts or zwitterions, though there have been successful studies which make allowance for these deficiencies.86,87 The affordable density functionals such as PBE also have known problems with these types of systems.88–90 Furthermore, it is very challenging to have computational methods that are equally reliable for intramolecular dispersion effects91 and intermolecular dispersion extending through the range of separations sampled in crystal structures, but this balance underlies the observed preference for flexible molecules to pack in extended crystal structures.92 The large dispersion contributions make the energies very density dependent, as well as being sensitive to conformational distortion and the stronger more directional interactions such as hydrogen bonding.
The phonon calculations within the Ψcrys approach, which are only affordable using DFTB3-D3, are conceptually different from the rigid-body Ψmol approach, in including effects for molecules having many molecular modes that are of comparable frequency to the lattice modes.41 The use of DFTB3-D3 accounts for differences in the molecular modes within different crystalline geometries. This leads to an even larger spread in Fvib values than with the rigid-body model, which already shows a range of ΔFvib that is comparable with polymorph energy differences,4 and was estimated to reorder the calculated stability of about 9% of over 500 observed pairs of polymorphs.80 This raises a question as to whether thermal effects are likely to be more significant in determining the relative thermodynamic stability of pharmaceutical polymorphs than for more rigid molecules, particularly when there is a larger range of densities amongst the PPMs. DFTB3-D3 calculates all phonon modes within the specific crystal in a reasonable timeframe, and these can be added to Elatt calculated with ΨPBE0+FITmol or a better periodic DFT-D method.70,93,94 The disadvantages of a poorer potential energy surface need to be balanced with the problems of converging energies with the size of the supercell to equivalent accuracy for different polymorphs demonstrated in this study.95 Even if it were possible to calculate completely reliable harmonic modes, which the current results in Fig. 5 show has yet to be achieved, thermal expansion is likely to be important for both absolute free energies65 and the differences in thermal expansion between polymorphs, which will affect the relative free energies.41,96 These estimates assume that the (quasi)-harmonic model is equally adequate for all polymorphs, which is questionable for larger molecules where methyl groups may be rotating and phenyl rings may have different large amplitude motions, depending on the packing. Hence, the potential energy surface should be explored more explicitly, for example by molecular dynamics simulations,97,98 as none of the methodologies currently available can fully describe all the possible thermal effects that can affect crystal structures and their relative free energy ranking.
Fig. 5 Relative energies of the polymorphs of XXIII calculated in this study compared with those reported by the participants of the 6th Blind Test.1 Note that values linked by dashed lines denote the changes from adding free energy estimates, with the group identifier in parentheses, and R denoting groups which only re-ranked the crystal structures. |
Many of the challenges in CSP studies are illustrated by the contrast between the crystal energy landscapes of XX and XXIII in Fig. 3, which from the chemical diagrams look like similar extended pharmaceutical molecules. The crystal energy landscape of molecule XX represents the simplest outcome of a CSP study, with a clear prediction of one crystal structure being more stable than any of its competitors. This structural refinement has led to a larger energy gap than previously found with two different Ψmol approaches,50 using CrystalOptimizer (FCC) and a force-field (RCM) for modifying the molecular conformation in response to the packing forces. Both had the experimentally-known crystal structure as the global minimum in Elatt but with a margin of less than 1 kJ mol−1 from the second most favourable PPM. Comparing the quality of this landscape with those of the previous studies is impossible as only three structures among the lowest ten found with the RCM method were among the top ten when optimised with the FCC method. ESI Table 5† shows that seven of the ten lowest-energy FCC crystal structures are among the ten lowest energy ΨPBE0+FITmol crystal structures, while for RCM this is only true for the crystal structure that matches the experimental form (see ESI Table 8†). The sensitivity of energies to the Elatt model is further shown by a generally very effective Ψcrys methodology developed by Neumann et al.21,24,99–101 having the experimental crystal structure ranked 7th,27 although that search included some Z′ = 2 crystal structures. Some of these Z′ = 2 structures also appear to be highly competitive when optimised with DFTB3-D3 and ΨPBE0+FITmol, as shown in ESI Table 9.† Nevertheless in our study the structure matching the only known experimental form is calculated to be the most stable by approximately 3 kJ mol−1, and there are relatively few alternatives to be considered as possible metastable polymorphs.
In contrast, the crystal energy landscape of XXIII has successfully found the three Z′ = 1 polymorphs, but amongst a plethora of competitive Z′ = 1 structures. Two further Z′ = 2 polymorphs are known from the industrial polymorph screening. Only form B is among the lowest energy crystal structures, while forms A and D are much higher in energy amongst many other structures of similar energy and density. Comparing these results with the sensitivity of the known polymorphs to different energy models, Fig. 5 suggests that the energy differences would have been reduced if the final energy optimisation had been performed using a good periodic DFT-D method, like TPSS-D3,102 PBE-MBD98 or B86bPBE-XDM.94,103 However, this contrasts with experimental stabilities from slurrying data, where form A is the most stable at 257 K and form D at 293 K.1 Overall, the sensitivity of the energies of the known forms of XXIII highlights the challenges of modelling the thermodynamics of the organic solid state. The contrast between the crystal energy landscapes of XX and XXIII emphasises the need for more CSP studies to be performed in collaboration with experimentalists in industry and academia.
Footnotes |
† Electronic supplementary information (ESI) available: Full details of results for each molecule. See DOI: 10.1039/c8fd00010g |
‡ Current address: Institute for Physical Chemistry, University of Goettingen, Tammannstr. 6, 37077 Goettingen, Germany. |
This journal is © The Royal Society of Chemistry 2018 |