Modelling of crystal structure of cis-1,2,3,6 and 3,4,5,6-tetrahydrophthalic anhydrides using lattice energy calculations

Lattice energy calculations using a model potential were performed to model the crystal structures of cis-1,2,3,6- and 3,4,5,6-tetrahydrophthalic (THP) anhydrides. The optimized molecular models using the DFT method at the B3LYP/6-31G** level were found consistent with the available experimental evidence and allowed all differences observed in crystal packing between cis-1,2,3,6- and 3,4,5,6-THP anhydrides to be reproduced. Calculations provide evidence for the presence of dipole–dipole C=O?C=O intermolecular interactions and support the idea that the molecules distort from their ideal geometries, improving packing in both crystals. The search for minima in the lattice energy of both crystals amongst the more common space groups with Z’?=?1, using a simulated annealing crystal structure prediction procedure followed by lattice energy minimization showed that the observed structure of 3,4,5,6-THP anhydride (Z’?=?2) is the thermodynamically most stable, and allowed us to justify why 3,4,5,6-THP anhydride crystallizes in such a complex structure with 16 molecules in the unit cell. The computational model was successful in predicting the second observed form at 173 K for cis-1,2,3,6-THP anhydride as a polymorph, and could predict several hypothetical structures with Z’?=?1 that appear competitive with the observed structures. The results of phonon estimates of zero point intermolecular vibrational energy and entropy suggest that crystal structures of cis-1,2,3,6-THP anhydride cannot be predicted solely on the basis of lattice energy; factors other than thermodynamics favor the observed structures

Synergy of solid-state NMR, single-crystal X-ray diffraction, and crystal structure prediction methods : a case study of teriflunomide (TFM)

In this work, for the first time, we present the X-ray diffraction crystal structure and spectral properties of a new, room-temperature polymorph of teriflunomide (TFM), CSD code 1969989. As revealed by DSC, the low-temperature TFM polymorph recently reported by Gunnam et al. undergoes a reversible thermal transition at −40 °C. This reversible process is related to a change in Z’ value, from 2 to 1, as observed by variable-temperature 1H–13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallographic system is preserved (triclinic). Two-dimensional 13C–1H and 1H–1H double-quantum MAS NMR spectra are consistent with the new room-temperature structure, including comparison with GIPAW (gauge-including projector augmented waves) calculated NMR chemical shifts. A crystal structure prediction procedure found both experimental teriflunomide polymorphs in the energetic global minimum region. Differences between the polymorphs are seen for the torsional angle describing the orientation of the phenyl ring relative to the planarity of the TFM molecule. In the low-temperature structure, there are two torsion angles of 4.5 and 31.9° for the two Z’ = 2 molecules, while in the room-temperature structure, there is disorder that is modeled with ∼50% occupancy between torsion angles of −7.8 and 28.6°. These observations are consistent with a broad energy minimum as revealed by DFT calculations. PISEMA solid-state NMR experiments show a reduction in the C–H dipolar coupling in comparison to the static limit for the aromatic CH moieties of 75% and 51% at 20 and 40 °C, respectively, that is indicative of ring flips at the higher temperature. Our study shows the power of combining experiments, namely DSC, X-ray diffraction, and MAS NMR, with DFT calculations and CSP to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical molecules

Computational crystal structure prediction and experimental characterisation of organic salts

Approximately half of all pharmaceutical drugs are marketed as salts. This thesis pioneers the application of computational crystal structure prediction to organic salts containing the commonly used chloride or carboxylate counterions, and assesses the extent to which the theoretical calculations can be used to aid experimental efforts targeting organic salts. A screen for multi-component solid forms of pyridine and 4- dimethylaminopyridine (DMAP) using a range of dicarboxylic acids led to one novel cocrystal of pyridine and six novel salts of DMAP. All novel crystal structures were solved using single crystal X-ray diffraction. At a simplistic level, salts differ from cocrystals in the position of the acidic proton within the crystal. For a selected set of structures, periodic ab initio calculations were shown to be useful in suggesting the observed N+-H (salt) or O-H (cocrystal) covalent bond as the preferred atomic connectivity. Modelling the same crystal structures by lattice energy minimisation using a distributed multipole based electrostatic model proved successful if the correct proton connectivity was used. The observed structures of a model salt, cocrystal and disordered salt-cocrystal system were found to be the most stable or almost equienergetic with the most stable structure in the predicted crystal energy landscapes. When the predictions were repeated using molecular structures with the wrong proton connectivity, the energetic ranking of the structure got worse. The computational model of crystal structure prediction was successfully used to rationalise the different polymorphic and hydration behaviour of the pharmacologically active amantadine hydrochloride and memantine hydrochloride salts. Finally, a similar methodology was applied to 1,8-naphthyridinium fumarate and the calculations performed as part of the fifth international blind test of crystal structure prediction. Overall, the success in modelling the crystal structures of carboxylate and chloride salts illustrates the promise of crystal structure prediction in aiding experimental efforts of organic salt selection