COSMOlogic GmbH

Stuttgart, Germany

COSMOlogic GmbH

Stuttgart, Germany
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Abramov Y.A.,Pfizer | Loschen C.,COSMOlogic GmbH | Klamt A.,COSMOlogic GmbH | Klamt A.,University of Regensburg
Journal of Pharmaceutical Sciences | Year: 2012

It is demonstrated that the fluid-phase thermodynamics theory conductor-like screening model for real solvents (COSMO-RS) as implemented in the COSMOtherm software can be used for accurate and efficient screening of coformers for active pharmaceutical ingredient (API) cocrystallization. The excess enthalpy, Hex, between an API-coformer mixture relative to the pure components reflects the tendency of those two compounds to cocrystallize. Thus, predictive calculations may be performed with decent effort on a large set of molecular data in order to identify potentially new cocrystal systems. In addition, it is demonstrated that COSMO-RS theory allows reasonable ranking of coformers for API solubility improvement. As a result, experiments may be focused on those coformers, which have an increased probability of cocrystallization, leading to the largest improvement of the API solubility. In a similar way as potential coformers are identified for cocrystallization, solvents that do not tend to form solvates may be determined based on the highest Hexs with the API. The approach was successfully tested on tyrosine kinase inhibitor axitinib, which has a propensity to form relatively stable solvated structures with the majority of common solvents, as well as on thiophanate-methyl and thiophanate-ethyl benzimidazole fungicides, which form channel solvates. © 2012 Wiley Periodicals, Inc.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: NMP-20-2014 | Award Amount: 3.67M | Year: 2015

The lifetime, reliability, and efficiency of organic light emitting diodes (OLED) are critical factors precluding a number of novel devices from entering the market. Yet, these stability issues of OLEDs are poorly understood due to their notorious complexity, since multiple degradation and failure channels are possible at different length- and timescales. Current experimental and theoretical models of OLED stability are, to a large extent, empirical. They do not include information about the molecular and meso-scales, which prevents their integration into the workflow of the industrial R&D compound design. It is the idea of this project to integrate various levels of theoretical materials characterization into a single software package, to streamline the research workflows in order for the calculations to be truly usable by materials engineers, complementary to experimental measurements. Towards this goal, this project brings together the academic and industrial expertise of the leading experimental and theoretical groups in the field of organic semiconductors.


Klamt A.,COSMOlogic GmbH | Klamt A.,University of Regensburg
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2011

The conductor-like screening model COSMO, a variant of the dielectric continuum solvation models, has become very popular due to its algorithmic simplicity, numerical stability, and its great insensitivity with respect to outlying charge errors. The advanced model COSMO-RS, i.e., COSMO for realistic solvation, is a statistical thermodynamics theory based on COSMO polarization charge densities, which overcomes many of the limitations and theoretical shortcomings of dielectric continuum models. Due to its ability to treat mixtures at variable temperatures, it has become very popular in chemical engineering and in wide areas of physical and medicinal chemistry. COSMO-RS currently may be considered as the most accurate model for the prediction of solvation energies. This article provides a short description of the basic concepts of both the models, of the differences with other solvation models and of their application areas. Finally, direct COSMO-RS, a recent direct integration of the COSMO-RS concept into quantum chemical calculations, is briefly described. © 2011 John Wiley & Sons, Ltd.


Klamt A.,COSMOlogic GmbH | Klamt A.,University of Regensburg | Eckert F.,COSMOlogic GmbH | Arlt W.,Sudan University of Science and Technology
Annual Review of Chemical and Biomolecular Engineering | Year: 2010

The conductor-like screening model for realistic solvation (COSMO-RS) method has been established as a novel way to predict thermophysical data for liquid systems and has become a frequently used alternative to force field - based molecular simulation methods on one side and group contribution methods on the other. Through its unique combination of a quantum chemical treatment of solutes and solvents with an efficient statistical thermodynamics procedure for the molecular surface interactions, it enables the efficient calculation of many properties that other methods can barely predict. This review presents a short delineation of the theory, the application potential and limitations of COSMO-RS, and its most important application areas. Copyright © 2010 by Annual Reviews. All rights reserved.


Loschen C.,COSMOlogic GmbH | Klamt A.,COSMOlogic GmbH | Klamt A.,University of Regensburg
Journal of Pharmacy and Pharmacology | Year: 2015

Objectives The fact that novel drug candidates are becoming increasingly insoluble is a major problem of current drug development. Computational tools may address this issue by screening for suitable solvents or by identifying potential novel cocrystal formers that increase bioavailability. In contrast to other more specialized methods, the fluid phase thermodynamics approach COSMO-RS (conductor-like screening model for real solvents) allows for a comprehensive treatment of drug solubility, solvate and cocrystal formation and many other thermodynamics properties in liquids. This article gives an overview of recent COSMO-RS developments that are of interest for drug development and contains several new application examples for solubility prediction and solvate/cocrystal screening. Methods For all property predictions COSMO-RS has been used. The basic concept of COSMO-RS consists of using the screening charge density as computed from first principles calculations in combination with fast statistical thermodynamics to compute the chemical potential of a compound in solution. Key finding The fast and accurate assessment of drug solubility and the identification of suitable solvents, solvate or cocrystal formers is nowadays possible and may be used to complement modern drug development. Efficiency is increased by avoiding costly quantum-chemical computations using a database of previously computed molecular fragments. Summary COSMO-RS theory can be applied to a range of physico-chemical properties, which are of interest in rational crystal engineering. Most notably, in combination with experimental reference data, accurate quantitative solubility predictions in any solvent or solvent mixture are possible. Additionally, COSMO-RS can be extended to the prediction of cocrystal formation, which results in considerable predictive accuracy concerning coformer screening. In a recent variant costly quantum chemical calculations are avoided resulting in a significant speed-up and ease-of-use. © 2015 Royal Pharmaceutical Society.


Renz M.,TU Berlin | Kess M.,TU Berlin | Diedenhofen M.,COSMOlogic GmbH | Klamt A.,COSMOlogic GmbH | Kaupp M.,TU Berlin
Journal of Chemical Theory and Computation | Year: 2012

A recently proposed quantum-chemical protocol for the description of the character of organic mixed-valence (MV) compounds, close from both sides to the localized/delocalized borderline, is evaluated and extended for a series of dinitroaryl radical anions 1-6. A combination of global hybrid functionals with exact-exchange admixtures of 35% (BLYP35) or 42% (BMK) with appropriate solvent modeling allows an essentially quantitative treatment of, for example, structural symmetry-breaking in Robin/Day class II systems, thermal electron transfer (ET) barriers, and intervalence charge-transfer (IV-CT) excitation energies, while covering also the delocalized class III cases. Global hybrid functionals with lower exact-exchange admixtures (e.g., B3LYP, M05, or M06) provide a too delocalized description, while functionals with higher exact-exchange admixtures (M05-2X, M06-2X) provide a too localized one. The B2PLYP double hybrid gives reasonable structures but far too small barriers in class II cases. The CAM-B3LYP range hybrid gives somewhat too high ET barriers and IV-CT energies, while the range hybrids ωB97X and LC-BLYP clearly exhibit too much exact exchange. Continuum solvent models describe the situation well in most aprotic solvents studied. The transition of 1,4-dinitrobenzene anion 1 from a class III behavior in aprotic solvents to a class II behavior in alcohols is not recovered by continuum solvent models. In contrast, it is treated faithfully by the novel direct conductor-like screening model for real solvents (D-COSMO-RS). The D-COSMO-RS approach, the TURBOMOLE implementation of which is reported, also describes accurately the increased ET barriers of class II systems 2 and 3 in alcohols as compared to aprotic solvents and can distinguish at least qualitatively between different aprotic solvents with identical or similar dielectric constants. The dominant role of the solvent environment for the ET character of these MV radical anions is emphasized, as in contrast to some previous computational suggestions essentially all of the present systems have delocalized class III character in the gas phase. The present approach allows accurate estimates from the gas phase to aprotic and protic solvent environments, without the need for explicit ab initio molecular dynamics simulations, and without artificial constraints. © 2012 American Chemical Society.


Diedenhofen M.,COSMOlogic GmbH | Klamt A.,COSMOlogic GmbH
Fluid Phase Equilibria | Year: 2010

In its first applications to ionic liquids the COSMO-RS method has shown to yield good qualitative and satisfying quantitative predictions for the activity coefficients of neutral compounds in ionic liquids and for binary mixtures of ionic liquids and neutral solvents. Since this success was achieved predictively, i.e. without any special parameterization, COSMO-RS since then has become a widely used and efficient tool for the prediction and screening of ionic liquid properties. In this article we give an overview of the various approaches and methodological differences used in this context by different groups. © 2010 Elsevier B.V. All rights reserved.


Hellweg A.,COSMOlogic GmbH
Journal of Computational Chemistry | Year: 2013

For the understanding and prediction of chemical reactions, detailed knowledge of the minimum energy path between reactants and transition state is of utmost importance. Stewart et al. (J. Comput. Chem. 1987, 8, 1117) proposed the usage of molecular trajectories calculated from Newton's equations of motion for an efficient reaction path following. Two operational modes are possible thereby: intrinsic (IRC) and dynamic reaction coordinate calculations (DRC). The technical difference between these modes is that in an IRC calculation the kinetic energy of the nuclei is quenched while the total energy is conserved in DRC calculations. In this work, a heuristic control methodology of atomic kinetic energies in DRC calculations using fuzzy logic is proposed. A diversified test set of 10 reactions has been collected to examine the performance of this approach. Fuzzy rule-based models are found to be a convenient way to make the determination of accessible paths of chemical reactions computationally efficient. © 2013 Wiley Periodicals, Inc.


Patent
COSMOlogic GmbH | Date: 2012-05-02

The invention relates to a computer-based method for generating a three-dimensional quantitative structure-activity relationship comprising the steps of a) providing a set of molecules with known binding constants or physiological activity data and information of the structure of said molecules, b) aligning the molecules to achieve maximum local similarity of molecular interaction regions that are common to the set of molecules, c) providing a surface polarity descriptor of the molecular surface for the set of molecules d) projecting the surface polarity descriptor to a fixed three-dimensional grid, wherein the same three-dimensional grid is used for all molecules and wherein the projection involves the use of local surface property histograms, mathematical equivalents thereof or derivatives thereof, and e) performing a molecular field analysis or an equivalent statistical analysis in order to derive a predictive model for the binding constant or physiological activity, wherein the molecular field analysis or the equivalent statistical analysis are at least partly based on the projection of the surface polarity descriptor to the three-dimensional grid.


Hellweg A.,COSMOlogic GmbH
Journal of Chemical Physics | Year: 2011

The accuracy of dipole moments calculated from wave function methods based on second-order perturbation theory is investigated in the ground and electronically excited states. Results from the approximate coupled-cluster singles-and-doubles model, CC2, Mller-Plesset perturbation theory, MP2, and the algebraic diagrammatic construction through second-order, ADC(2), are discussed together with the spin-component scaled and the scaled opposite-spin variants of these methods. The computed dipole moments show a very good correlation with data from high-resolution spectroscopy. Compared to the unscaled methods, the spin-component scaling increases the accuracy of the results and improves the robustness of the calculations. An accuracy about 0.2 to 0.1 D in the ground state and about 0.3 to 0.2 D in the electronically excited states can be achieved with these approaches. © 2011 American Institute of Physics.

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