Avant garde Materials Simulation Deutschland GmbH

Freiburg, Germany

Avant garde Materials Simulation Deutschland GmbH

Freiburg, Germany
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Li X.,Copenhagen University | Neumann M.A.,Avant garde Materials Simulation Deutschland GmbH | Van De Streek J.,Copenhagen University
IUCrJ | Year: 2017

Motional averaging has been proven to be significant in predicting the chemical shifts in ab initio solid-state NMR calculations, and the applicability of motional averaging with molecular dynamics has been shown to depend on the accuracy of the molecular mechanical force field. The performance of a fully automatically generated tailor-made force field (TMFF) for the dynamic aspects of NMR crystallography is evaluated and compared with existing benchmarks, including static dispersion-corrected density functional theory calculations and the COMPASS force field. The crystal structure of free base cocaine is used as an example. The results reveal that, even though the TMFF outperforms the COMPASS force field for representing the energies and conformations of predicted structures, it does not give significant improvement in the accuracy of NMR calculations. Further studies should direct more attention to anisotropic chemical shifts and development of the method of solid-state NMR calculations. © 2017.

Neumann M.A.,Avant garde Materials Simulation Deutschland GmbH | Van De Streek J.,Copenhagen University | Fabbiani F.P.A.,University of Gottingen | Hidber P.,Hoffmann-La Roche | Grassmann O.,Hoffmann-La Roche
Nature Communications | Year: 2015

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib. © 2015 Macmillan Publishers Limited. All rights reserved.

Chan H.C.S.,University of Bradford | Chan H.C.S.,Novartis | Kendrick J.,University of Bradford | Neumann M.A.,Avant garde Materials Simulation Deutschland GmbH | Leusen F.J.J.,University of Bradford
CrystEngComm | Year: 2013

Co-crystallisation of a drug with another molecule to form a new crystalline material is an appealing route to enhance physical properties. Despite mounting research effort, there is still considerable uncertainty whether a given co-crystal will form. Previous attempts to use lattice energy calculations to investigate whether a potential co-crystal is thermodynamically more stable than its pure co-former crystals have been inconclusive. In the present study, dispersion-corrected density functional theory is used to minimise the lattice energies of all known co-crystals and salts of nicotinamide, isonicotinamide and picolinamide, and their corresponding neutral co-formers (excluding any organometallic compounds). Out of the resulting 102 co-crystals and salts, 99 (97%) are found to be more stable than their corresponding co-formers. In addition, full crystal structure prediction studies show that two paracetamol co-crystals are very unstable in comparison to their co-formers, thus explaining why these co-crystals have not been observed experimentally. These results demonstrate that a simple yet accurate thermodynamic approach can predict reliably whether a co-crystal can be formed. © 2013 The Royal Society of Chemistry.

Kendrick J.,University of Bradford | Stephenson G.A.,Eli Lilly and Company | Neumann M.A.,Avant garde Materials Simulation Deutschland GmbH | Leusen F.J.J.,University of Bradford
Crystal Growth and Design | Year: 2013

Crystal structure prediction methods have been used to explore the potential energy landscape for crystals of a melatonin agonist (MA). All known experimental polymorphs were found in the search for crystal packing alternatives with a single molecule in the asymmetric unit, and the predicted order of stability agrees with experiment. The crystal structure corresponding to the global minimum has not been observed experimentally, but analysis of the crystal structures of similar molecules in the Cambridge Structural Database (CSD) indicates that the packing motif present in the predicted structure is also found in nature. To date it has not been experimentally possible to crystallize the most stable polymorph of the biologically active R-enantiomer, whereas the S-enantiomer readily crystallizes in the stable form. Analysis of the results shows that this polymorph has an uncommon packing motif which is found just once among the 12 lowest energy predicted structures but is seen in two crystal structures of MA-like molecules whose structures are stored in the CSD. On the basis of the calculations and comparisons with experimental crystal structures, suggestions are made as to possible routes for crystallizing the, as yet unknown, polymorph of MA, which corresponds to the predicted structure with the lowest lattice energy. © 2013 American Chemical Society.

Beko S.L.,Goethe University Frankfurt | Czech C.,Goethe University Frankfurt | Neumann M.A.,Avant garde Materials Simulation Deutschland GmbH | Schmidt M.U.,Goethe University Frankfurt
Zeitschrift fur Kristallographie - Crystalline Materials | Year: 2015

The crystal structures of 4-chloro-5-methyl-2-ammoniobenzenesulfonate and of the corresponding derivatives 4,5-dimethyl- and 4,5-dichloro-2-ammoniobenzenesulfonates have been determined from laboratory X-ray powder diffraction data. The tautomeric state of all three compounds could also be unequivocally determined from laboratory data, using careful Rietveld refinements. The tautomeric state was confirmed by IR spectroscopy. The compounds are neither isostructural to each other nor to the 5-chloro-4-methyl derivate, despite the similar size of the chloro and methyl substituents. The influence of the chloro and methyl substituents on the packing and on the thermal stability is demonstrated. All crystal structures were confirmed by dispersion-corrected DFT calculations. For the 4-chloro-5-methyl and the 4,5-dichloro derivatives the DFT calculations indicated that the observed polymorph should not be the thermodynamical one. However, no other polymorphs could be found in experimental polymorph screening, even using seeding with the corresponding isostructural phases. Obviously the DFT methods need further improvements. © 2015 by De Gruyter 2015.

Van De Streek J.,Copenhagen University | Neumann M.A.,Avant garde Materials Simulation Deutschland GmbH
Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials | Year: 2014

In 2010 we energy-minimized 225 high-quality single-crystal (SX) structures with dispersion-corrected density functional theory (DFT-D) to establish a quantitative benchmark. For the current paper, 215 organic crystal structures determined from X-ray powder diffraction (XRPD) data and published in an IUCr journal were energy-minimized with DFT-D and compared to the SX benchmark. The on average slightly less accurate atomic coordinates of XRPD structures do lead to systematically higher root mean square Cartesian displacement (RMSCD) values upon energy minimization than for SX structures, but the RMSCD value is still a good indicator for the detection of structures that deserve a closer look. The upper RMSCD limit for a correct structure must be increased from 0.25Å for SX structures to 0.35Å for XRPD structures; the grey area must be extended from 0.30 to 0.40Å. Based on the energy minimizations, three structures are re-refined to give more precise atomic coordinates. For six structures our calculations provide the missing positions for the H atoms, for five structures they provide corrected positions for some H atoms. Seven crystal structures showed a minor error for a non-H atom. For five structures the energy minimizations suggest a higher space-group symmetry. For the 225 SX structures, the only deviations observed upon energy minimization were three minor H-atom related issues. Preferred orientation is the most important cause of problems. A preferred-orientation correction is the only correction where the experimental data are modified to fit the model. We conclude that molecular crystal structures determined from powder diffraction data that are published in IUCr journals are of high quality, with less than 4% containing an error in a non-H atom. © 2014.

Beko S.L.,Goethe University Frankfurt | Thoms S.D.,Goethe University Frankfurt | Bruning J.,Goethe University Frankfurt | Alig E.,Goethe University Frankfurt | And 4 more authors.
Zeitschrift fur Kristallographie | Year: 2010

The title compound, also called CLT acid, is an industrial intermediate in the synthesis of laked red azo pigments for newspaper printing. Solid-state NMR and IR experiments revealed the compound to exist as the zwitterionic tautomer in the solid state. The crystal structure was solved from X-ray powder diffraction data by means of real-space methods using the program DASH 3.1. Subsequently the structure was refined by the Rietveld method with TOPAS 4.1. The zwitterionic tautomer gave better confidence values than the non-zwitterionic tautomer. Finally the structure was confirmed by dispersion-corrected density-functional calculations. The compound crystallises in the monoclinic space group Ia, Z = 4 with a = 5.49809(7) Å b = 32.8051(5) Å c = 4.92423(7) Å, b = 93.5011(7)β and V = 886.50(2) Å3. The molecules form a herringbone pattern with a double layer structure consisting of alternating polar and non-polar layers. Within the polar layers hydrogen bonds and ionic interactions are dominant, whereas the fragments in the non-polar layers are connected by van der Waals interactions. © Oldenbourg Wissenschaftsverlag, München.

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