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Crystal Polymorphism of Substituted Monocyclic Aromatics
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology.ORCID iD: 0000-0002-6647-3308
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Stockholm: KTH , 2009. , p. xiv, 73
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2009:26
Keyword [en]
Crystallization, polymorphism, thermodynamics, kinetics, solubility, nucleation, crystal structure prediction, lattice energy, enthalpy, entropy, molecular mechanics, quantum mechanics, electrostatic potential, force field
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-10501ISBN: 978-91-7415-342-2 (print)OAI: oai:DiVA.org:kth-10501DiVA, id: diva2:218167
Presentation
2009-06-11, K1, KTH, Teknikringen 56, Stockholm, 11:00 (Swedish)
Opponent
Supervisors
Available from: 2009-05-26 Created: 2009-05-19 Last updated: 2010-10-29Bibliographically approved
List of papers
1. Force Fields and Point Charges for Crystal Structure Modeling
Open this publication in new window or tab >>Force Fields and Point Charges for Crystal Structure Modeling
2009 (English)In: Industrial & Engineering Chemistry Research, ISSN 0888-5885, E-ISSN 1520-5045, Vol. 48, no 6, p. 2899-2912Article in journal (Refereed) Published
Abstract [en]

Molecular simulation is increasingly used by chemical engineers and industrial chemists in process and product development. In particular, the possibility to predict the structure and stability of potential polymorphs of a substance is of tremendous interest to the pharmaceutical and specialty chemicals industry. Molecular mechanics modeling relies on the use of parametrized force fields and methods of assigning point charges to the atoms in the molecules. In commercial molecular simulation software, a wide variety of such combinations are available, and there is a need for critical assessment of the capabilities of the different alternatives. In the present work, the performance of several molecular mechanics force fields combined with different methods for the assignment of atomic point charges have been examined with regard to their ability to calculate absolute crystal lattice energies and their capacity to identify the experimental structure as a minimum on the potential energy hypersurface. Seven small, aromatic monomolecular crystalline compounds are used in the evaluation. It is found that the majority of the examined methods cannot be used to reliably predict absolute lattice energies. The most promising results were obtained with the Pcff force field using integral charges, and the Dreiding force field using Gasteiger charges, both of which performed with an accuracy of the same order of magnitude as the variations in experimental lattice energies. Overall, it has been observed that the best results are achieved if the same force field method is used to relax the crystal structure and calculate the energy, and to optimize and calculate the energy of the gas phase molecule used for the correction for changes in molecular geometry. The Pcff and Compass force fields with integral charges have been found to predict relaxed structures closest to the experimental ones. In addition, five different methods for determining point charges fitted to the electrostatic potential (ESP charges), available in the same software, have been evaluated. For each method, the molecular geometries of 10 small, organic molecules were optimized, and ESP charges calculated and analyzed for linear correlation with a set of reference charges of an accepted standard method, HF/6-31G*. Dmol-3 gives charges that correlate well with the reference charge. The charges from Vamp are not linearly scalable to the HF/6-31G*-level, which is attributed partly to the geometry optimization but mainly to the calculation of the ESP and the subsequent charge fit.

Keyword
Chemical engineers, Compass force fields, Critical assessments, Crystalline compounds, Dreiding force fields, Electrostatic potentials, Force field methods, Force fields, Gas-phase molecules, Geometry optimizations, Hf/6-31g, In process, Industrial chemists, Integral charges, Lattice energies, Linear correlations, Molecular geometries, Molecular simulations, Order of magnitudes, Organic molecules, Point charges, Potential energy hyper surfaces, Specialty chemicals, Standard methods, Structure modeling
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-10496 (URN)10.1021/ie800502m (DOI)000264221600020 ()2-s2.0-65349108076 (Scopus ID)
Note

QC 20101029

Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically approved
2. Structural and energetic aspects of the differences between real and predicted polymorphs
Open this publication in new window or tab >>Structural and energetic aspects of the differences between real and predicted polymorphs
2010 (English)In: Crystal research and technology (1981), ISSN 0232-1300, E-ISSN 1521-4079, Vol. 45, no 8, p. 867-878Article in journal (Refereed) Published
Abstract [en]

In crystal structure prediction simulations based on lattice energy minimization, usually hundreds of structures within a reasonable range of lattice energy and density are found, whereas in practice, it is very rare to find more than a few polymorphs of the same compound. In the work presented here, this discrepancy is investigated from a structural and energetic point of view. 56 crystal structures of 26 polymorphic mono- and disubstituted aromatic compounds, extracted from the Cambridge Structural Database, have been analysed with respect to inter-polymorphic structural similarity. For comparison, potential crystal packing arrangements of the substances have been predicted with molecular mechanics simulations using a generic force field. The predicted structures are analysed with respect to structural features and similarity, and with respect to the number of structures and their lattice energy. It is found that the real polymorphs studied in this work tend to be structurally quite dissimilar with regard to hydrogen bonding and spatial packing of structural motifs, while many of the predicted structures of a given compound are very similar to each other. The results suggest that structure and lattice energy alone cannot explain why so few polymorphs are found in practice compared to the very large numbers predicted in simulations.

Keyword
polymorphism, crystallization
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-10499 (URN)10.1002/crat.201000205 (DOI)000280674600015 ()2-s2.0-77955754373 (Scopus ID)
Note
QC 20101029. Uppdaterad från Manuskript till Artikel (20101029). Tidigare titel:"Structural and Energetic Aspects of Real Versus Predicted Polymorphs".Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically approved
3. Thermodynamics and Nucleation Kinetics of m-Aminobenzoic Acid Polymorphs
Open this publication in new window or tab >>Thermodynamics and Nucleation Kinetics of m-Aminobenzoic Acid Polymorphs
2010 (English)In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 10, no 1, p. 195-204Article in journal (Refereed) Published
Abstract [en]

The polymorphism of m-aminobenzoic acid has been investigated. Two polymorphs have been identified and characterized by X-ray powder diffraction (XRPD), Fourier transform IR (FTIR), microscopy, and thermal analysis. The melting properties and isobaric heat capacities of both polymorphs have been determined calorimetrically, and the solubility of each polymorph in several solvents at different temperatures has been determined gravimetrically. The solid-state activity (i.e., the Gibbs free energy of fusion) of each polymorph has been determined through a comprehensive thermodynamic analysis based on experimental data. It is found that the polymorphs are enantiotropically related, with a stability transition temperature of 156.1 °0C. The published crystal structure belongs to the polymorph that is metastable at room temperature. Energytemperature diagrams of both polymorphs have been established by determining the free energy, enthalpy, and entropy of fusion as a function of temperature. A total of 300 cooling crystallizations have been carried out at constant cooling rate using different saturation temperatures and solvents, and the visible onset of primary nucleation was recorded. The results show that for this substance the polymorph that will nucleate depends chiefly on the solvent. In water and methanol solutions, the stable form I was obtained in all experiments, whereas in acetonitrile, a majority of nucleation experiments resulted in the isolation of the metastable form II. It is shown how this can be rationalized by analysis of solubility, solution speciation, and nucleation relationships. The importance of carrying out multiple experiments at identical conditions in nucleation studies of polymorphic systems is demonstrated.

Keyword
DISSOCIATION-CONSTANTS, AMINO-ACIDS, META, ZWITTERION
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-10500 (URN)10.1021/cg900850u (DOI)000274757100033 ()2-s2.0-74049160883 (Scopus ID)
Note

QC 20101029. Uppdaterad från Manuskript till Artikel (20101029).

Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2017-12-13Bibliographically approved
4. Molecular Simulations to Predict Experimental Polymorphs
Open this publication in new window or tab >>Molecular Simulations to Predict Experimental Polymorphs
2008 (English)In: Proceedings of the 17th International Symposium on Industrial Crystallization / 8th Conference on Crystal Growth of Organic Materials (Maastricht, NL), 2008, p. 1631-Conference paper, Published paper (Refereed)
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-10498 (URN)
Conference
ISIC 17 - CGOM 8, Maastricht (the Netherlands), September 14-17
Note
QC 20101029Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2011-05-27Bibliographically approved

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