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Nanoscale ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32044911


Here, we show that the development of nuclei and subsequent growth of a molecular organic crystal system can be induced by electron beam irradiation by exploiting the radiation chemistry of the carrier solvent. The technique of Liquid Cell Electron Microscopy was used to probe the crystal growth of flufenamic acid; a current commercialised active pharmaceutical ingredient. This work demonstrates liquid phase electron microscopy analysis as an essential tool for assessing pharmaceutical crystal growth in their native environment while giving insight into polymorph identification of nano-crystals at their very inception. Possible mechanisms of crystal nucleation due to the electron beam with a focus on radiolysis are discussed along with the innovations this technique offers to the study of pharmaceutical crystals and other low contrast materials.

J Phys Chem A ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31951408


Understanding why crystallization in strong magnetic fields can lead to new polymorphs requires methods to calculate the diamagnetic response of organic molecular crystals. We develop the calculation of the macroscopic diamagnetic susceptibility tensor, χcryst, for organic molecular crystals using periodic density functional methods. The crystal magnetic susceptibility tensor, χcryst, for all experimentally known polymorphs, and its molecular counterpart, χmol, are calculated for flexible pharmaceuticals such as carbamazepine, flufenamic acid, and chalcones, and rigid molecules, such as benzene, pyridine, acridine, anthracene, and coronene, whose molecular magnetic properties have been traditionally studied. A tensor addition method is developed to approximate the crystal diamagnetic susceptibility tensor, χcryst, from the molecular one, χmol, giving good agreement with those calculated directly using the more costly periodic density functional method for χcryst. The response of pharmaceutical molecules and crystals to magnetic fields, as embodied by χcryst, is largely determined by the packing in the crystal, as well as the molecular conformation. The anisotropy of χcryst can vary considerably between polymorphs though the isotropic terms are fairly constant. The implications for developing a computational method for predicting whether crystallization in a magnetic field could produce a novel or different polymorph are discussed.

J Am Chem Soc ; 141(35): 13887-13897, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31394896


The solid form screening of galunisertib produced many solvates, prompting an extensive investigation into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape and assess the risk of late-appearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes.

Acta Crystallogr B ; 67(Pt 6): 535-51, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22101543


Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories - a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.

Cristalografia por Raios X/métodos , Compostos Orgânicos/química , Bases de Dados Factuais , Modelos Moleculares
Chem Commun (Camb) ; 47(25): 7074-6, 2011 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-21614395


A computationally assisted approach has enabled the first catemeric polymorph of carbamazepine (form V) to be selectively formed by templating the growth of carbamazepine from the vapour phase onto the surface of a crystal of dihydrocarbamazepine form II.

Anticonvulsivantes/química , Carbamazepina/química , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Termodinâmica
Phys Chem Chem Phys ; 12(30): 8478-90, 2010 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-20607186


Crystal structure prediction for organic molecules requires both the fast assessment of thousands to millions of crystal structures and the greatest possible accuracy in their relative energies. We describe a crystal lattice simulation program, DMACRYS, emphasizing the features that make it suitable for use in crystal structure prediction for pharmaceutical molecules using accurate anisotropic atom-atom model intermolecular potentials based on the theory of intermolecular forces. DMACRYS can optimize the lattice energy of a crystal, calculate the second derivative properties, and reduce the symmetry of the spacegroup to move away from a transition state. The calculated terahertz frequency k = 0 rigid-body lattice modes and elastic tensor can be used to estimate free energies. The program uses a distributed multipole electrostatic model (Q, t = 00,...,44s) for the electrostatic fields, and can use anisotropic atom-atom repulsion models, damped isotropic dispersion up to R(-10), as well as a range of empirically fitted isotropic exp-6 atom-atom models with different definitions of atomic types. A new feature is that an accurate model for the induction energy contribution to the lattice energy has been implemented that uses atomic anisotropic dipole polarizability models (alpha, t = (10,10)...(11c,11s)) to evaluate the changes in the molecular charge density induced by the electrostatic field within the crystal. It is demonstrated, using the four polymorphs of the pharmaceutical carbamazepine C(15)H(12)N(2)O, that whilst reproducing crystal structures is relatively easy, calculating the polymorphic energy differences to the accuracy of a few kJ mol(-1) required for applications is very demanding of assumptions made in the modelling. Thus DMACRYS enables the comparison of both known and hypothetical crystal structures as an aid to the development of pharmaceuticals and other speciality organic materials, and provides a tool to develop the modelling of the intermolecular forces involved in molecular recognition processes.