Papers by Andrei Kazantsev
Journal of Chemical Theory and Computation, Apr 8, 2009
We report a multistage lattice energy minimization methodology for generating stable packing arra... more We report a multistage lattice energy minimization methodology for generating stable packing arrangements of cocrystals containing flexible molecules. In the first approximation, the intermolecular electrostatic interactions are modeled with atomic charges and the molecular deformation energy is interpolated over a set of precomputed quantum mechanical values. At subsequent stages, the accuracy is improved by first using analytically rotated and then conformation-dependent multipole moments, computed from the isolated-molecule charge density, and "on-the-fly" quantum mechanical calculations to compute the intramolecular deformation energy. This multistage approach increases the efficiency of the search and establishes the molecule-dependent error due to the atomic charge representation of the charge density and the neglect of the conformational dependence of atomic multipole moments. The methodology is used to study the lattice energy landscapes of the cocrystals of 4-aminobenzoic acid with 2,2′-bipyridine and 4-nitrophenylacetic acid, as well as the single-component crystals. All single-component, experimentally determined crystal structures within the scope of the search were found at, or very close to, the global minimum. The experimental cocrystal with 2,2′-bipyridine is also predicted to be among the most stable packing arrangements. On the contrary, the lattice energy landscape of the cocrystal with 4-nitrophenylacetic acid contains several low energy structures that are more stable than the experimentally observed form and have different hydrogen bonding motifs. Overall, the methodology can provide worthwhile crystal energy landscapes for multicomponent organic solids and thereby contribute to understanding cocrystal formation.
Topics in current chemistry, 2014
The prediction of the possible crystal structure(s) of organic molecules is an important activity... more The prediction of the possible crystal structure(s) of organic molecules is an important activity for the pharmaceutical and agrochemical industries, among others, due to the prevalence of crystalline products. This chapter considers the general requirements that crystal structure prediction (CSP) methodologies need to fulfil in order to be able to achieve reliable predictions over a wide range of organic systems. It also reviews the current status of a multistage CSP methodology that has recently proved successful for a number of systems of practical interest. Emphasis is placed on recent developments that allow a reconciliation of conflicting needs for, on the one hand, accurate evaluation of the energy of a proposed crystal structure and on the other hand, comprehensive search of the energy landscape for the reliable identification of all low-energy minima. Finally, based on the experience gained from this work, current limitations and opportunities for further research in this area are identified. We also consider issues relating to the use of empirical models derived from experimental data in conjunction with ab initio CSP.
Wiley-VCH Verlag GmbH & Co. KGaA eBooks, Jun 27, 2011
... 10 1 CrystalOptimizer: An Efficient Algorithm for Lattice Energy Minimization dom, θr, and th... more ... 10 1 CrystalOptimizer: An Efficient Algorithm for Lattice Energy Minimization dom, θr, and the corresponding intramolecular energy, Eintra(θf), are obtained. In the inner optimization, DMACRYS [50, 55] is used to compute the minimum intermolecular energy, Uinter, and the ...
Elsevier eBooks, 2010
A three-stage lattice energy minimisation methodology is reported for the identification of stabl... more A three-stage lattice energy minimisation methodology is reported for the identification of stable crystal structures containing flexible molecules. The accuracy of the approach is improved from stage to stage by using increasingly accurate models, first by substituting an atomic ...
Towards crystal structure prediction of complex organic compounds – a report on the fifth blind test
A large proportion of organic molecular solids are obtained in crystalline form. A crystal is a s... more A large proportion of organic molecular solids are obtained in crystalline form. A crystal is a solid, in which molecules are packed in a long-range, regular ordered, repeating pattern extending in all three spatial dimensions (Fig. 1.1). Crystallization of a given compound does not always lead to the same crystal structure. Depending on the crystallization conditions, different packings of the same compound are often observed. This phenomenon is called polymorphism. The diversity in packing motifs arises from differences in spatial arrangements and/or conformations of molecules in crystals (Fig. 1.1). Polymorphs are found in many classes of molecular materials including, but not limited to, aromatic π -bonded systems, amino acids, amides, and carboxylic acids [3]. Because the underlying chemistry of the molecules in the crystals remains unchanged, all polymorphs have identical chemical properties. However, differences in molecular packings between polymorphs can lead to differences...
Journal of Chemical Theory and Computation, May 11, 2009
We report a multistage lattice energy minimization methodology for generating stable packing arra... more We report a multistage lattice energy minimization methodology for generating stable packing arrangements of cocrystals containing flexible molecules. In the first approximation, the intermolecular electrostatic interactions are modeled with atomic charges and the molecular deformation energy is interpolated over a set of precomputed quantum mechanical values. At subsequent stages, the accuracy is improved by first using analytically rotated and then conformation-dependent multipole moments, computed from the isolated-molecule charge density, and "on-the-fly" quantum mechanical calculations to compute the intramolecular deformation energy. This multistage approach increases the efficiency of the search and establishes the molecule-dependent error due to the atomic charge representation of the charge density and the neglect of the conformational dependence of atomic multipole moments. The methodology is used to study the lattice energy landscapes of the cocrystals of 4-aminobenzoic acid with 2,2'-bipyridine and 4-nitrophenylacetic acid, as well as the single-component crystals. All single-component, experimentally determined crystal structures within the scope of the search were found at, or very close to, the global minimum. The experimental cocrystal with 2,2'-bipyridine is also predicted to be among the most stable packing arrangements. On the contrary, the lattice energy landscape of the cocrystal with 4-nitrophenylacetic acid contains several low energy structures that are more stable than the experimentally observed form and have different hydrogen bonding motifs. Overall, the methodology can provide worthwhile crystal energy landscapes for multicomponent organic solids and thereby contribute to understanding cocrystal formation.
Acta Crystallographica Section B Structural Science, 2011
There is a multitude of possible formulation pathways for pharmaceutical compounds among which po... more There is a multitude of possible formulation pathways for pharmaceutical compounds among which polymorph, solvate, salt and cocrystal formation are the most common. Finding the optimal formulation by experimentation alone is often expensive and time consuming. In a quality by design environment, computational approaches can aid and direct the search for the best crystal form. We have recently developed a novel algorithm for the accurate minimization of lattice energy of crystals involving flexible organic molecules [1]. The algorithm makes use of multipole moments (up to hexadecapole level) for the calculation of the intermolecular electrostatic interactions. It derives its accuracy from the use of isolated-molecule quantum mechanical calculations for the computation of intramolecular energy and the electrostatic field around the molecule. The main novelty of the algorithm is the use of dynamically constructed and updated local approximate models (LAMs) which essentially make availa...
Topics in current chemistry, 2014
The prediction of the possible crystal structure(s) of organic molecules is an important activity... more The prediction of the possible crystal structure(s) of organic molecules is an important activity for the pharmaceutical and agrochemical industries, among others, due to the prevalence of crystalline products. This chapter considers the general requirements that crystal structure prediction (CSP) methodologies need to fulfil in order to be able to achieve reliable predictions over a wide range of organic systems. It also reviews the current status of a multistage CSP methodology that has recently proved successful for a number of systems of practical interest. Emphasis is placed on recent developments that allow a reconciliation of conflicting needs for, on the one hand, accurate evaluation of the energy of a proposed crystal structure and on the other hand, comprehensive search of the energy landscape for the reliable identification of all low-energy minima. Finally, based on the experience gained from this work, current limitations and opportunities for further research in this a...
Computer Aided Chemical Engineering, 2010
A three-stage lattice energy minimisation methodology is reported for the identification of stabl... more A three-stage lattice energy minimisation methodology is reported for the identification of stable crystal structures containing flexible molecules. The accuracy of the approach is improved from stage to stage by using increasingly accurate models, first by substituting an atomic ...
Volume 6: Molecular Systems Engineering, 2011
... 10 1 CrystalOptimizer: An Efficient Algorithm for Lattice Energy Minimization dom, θr, and th... more ... 10 1 CrystalOptimizer: An Efficient Algorithm for Lattice Energy Minimization dom, θr, and the corresponding intramolecular energy, Eintra(θf), are obtained. In the inner optimization, DMACRYS [50, 55] is used to compute the minimum intermolecular energy, Uinter, and the ...
International journal of pharmaceutics, Jan 14, 2011
The range of target structures in the fifth international blind test of crystal structure predict... more The range of target structures in the fifth international blind test of crystal structure prediction was extended to include a highly flexible molecule, (benzyl-(4-(4-methyl-5-(p-tolylsulfonyl)-1,3-thiazol-2-yl)phenyl)carbamate, as a challenge representative of modern pharmaceuticals. Two of the groups participating in the blind test independently predicted the correct structure. The methods they used are described and contrasted, and the implications of the capability to tackle molecules of this complexity are discussed.
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Papers by Andrei Kazantsev