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Structural, Kinetic and Thermodynamic Aspects of the Crystal Polymorphism of Substituted Monocyclic Aromatic Compounds
KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.ORCID iD: 0000-0002-6647-3308
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This work concerns the interrelationship between thermodynamic, kinetic and structural aspects of crystal polymorphism. It is both experimental and theoretical, and limited with respect to compounds to substituted monocyclic aromatics.

Two polymorphs of the compound m-aminobenzoic acid have been experimentally isolated and characterized by ATR-FTIR spectroscopy, X-ray powder diffraction and optical microscopy. In addition, two polymorphs of the compound m-hydroxybenzoic acid have been isolated and characterized by ATR-FTIR spectroscopy, high-temperature XRPD, confocal Raman, hot-stage and scanning electron microscopy. For all polymorphs, melting properties and specific heat capacity have been determined calorimetrically, and the solubility in several pure solvents measured at different temperatures with a gravimetric method. The solid-state activity (ideal solubility), and the free energy, enthalpy and entropy of fusion have been determined as functions of temperature for all solid phases through a thermodynamic analysis of multiple experimental data. It is shown that m-aminobenzoic acid is an enantiotropic system, with a stability transition point determined to be located at approximately 156°C, and that the difference in free energy at room temperature between the polymorphs is considerable. It is further shown that m-hydroxybenzoic acid is a monotropic system, with minor differences in free energy, enthalpy and entropy.

1393 primary nucleation experiments have been carried out for both compounds in different series of repeatability experiments, differing with respect to solvent, cooling rate, saturation temperature and solution preparation and pre-treatment. It is found that in the vast majority of experiments, either the stable or the metastable polymorph is obtained in the pure form, and only for a few evaluated experimental conditions does one polymorph crystallize in all experiments. The fact that the polymorphic outcome of a crystallization is the result of the interplay between relative thermodynamic stability and nucleation kinetics, and that it is vital to perform multiple experiments under identical conditions when studying nucleation of polymorphic compounds, is strongly emphasized by the results of this work.

The main experimental variable which in this work has been found to affect which polymorph will preferentially crystallize is the solvent. For m-aminobenzoic acid, it is shown how a significantly metastable polymorph can be obtained by choosing a solvent in which nucleation of the stable form is sufficiently obstructed. For m-hydroxybenzoic acid, nucleation of the stable polymorph is promoted in solvents where the solubility is high. It is shown how this partly can be rationalized by analysing solubility data with respect to temperature dependence.

By crystallizing solutions differing only with respect to pre-treatment and which polymorph was dissolved, it is found that the immediate thermal and structural history of a solution can have a significant effect on nucleation, affecting the predisposition for overall nucleation as well as which polymorph will preferentially crystallize.

A set of polymorphic crystal structures has been compiled from the Cambridge Structural Database. It is found that statistically, about 50% crystallize in the crystallographic space group P21/c. Furthermore, it is found that crystal structures of polymorphs tend to differ significantly with respect to either hydrogen bond network or molecular conformation.

Molecular mechanics based Monte Carlo simulated annealing has been used to sample different potential crystal structures corresponding to minima in potential energy with respect to structural degrees of freedom, restricted to one space group, for each of the polymorphic compounds. It is found that all simulations result in very large numbers of predicted structures. About 15% of the predicted structures have excess relative lattice energies of <=10% compared to the most stable predicted structure; a limit verified to reflect maximum lattice energy differences between experimentally observed polymorphs of similar compounds. The number of predicted structures is found to correlate to molecular weight and to the number of rotatable covalent bonds. A close study of two compounds has shown that predicted structures tend to belong to different groups defined by unique hydrogen bond networks, located in well-defined regions in energy/packing space according to the close-packing principle. It is hypothesized that kinetic effects in combination with this structural segregation might affect the number of potential structures that can be realized experimentally.

The experimentally determined crystal structures of several compounds have been geometry-optimized (relaxed) to the nearest potential energy minimum using ten different combinations of common potential energy functions (force fields) and techniques for assigning nucleus-centred point charges used in the electrostatic description of the energy. Changes in structural coordinates upon relaxation have been quantified, crystal lattice energies calculated and compared with experimentally determined enthalpies of sublimation, and the energy difference before and after relaxation computed and analysed. It is found that certain combinations of force fields and charge assignment techniques work reasonably well for modelling crystal structures of small aromatics, provided that proper attention is paid to electrostatic description and to how the force field was parameterized.

A comparison of energy differences for randomly packed as well as experimentally determined crystal structures before and after relaxation suggests that the potential energy function for the solid state of a small organic molecule is highly undulating with many deep, narrow and steep minima.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology , 2011. , xvi, 75, v p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2011:35
Keyword [en]
Polymorphism, crystallization, thermodynamics, kinetics, nucleation, crystallography, solubility, phase equilibria, polymorphic transformation, solution history, metastable zone, classical theory of nucleation, two-step theory of nucleation, cluster, crystal structure prediction, lattice energy, molecular mechanics, force field, electrostatic potential, potential energy hypersurface, m-aminobenzoic acid, m-hydroxybenzoic acid
National Category
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-33836ISBN: 978-91-7415-993-6OAI: oai:DiVA.org:kth-33836DiVA: diva2:418058
Public defence
2011-06-10, K1, Teknikringen 56, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20110527Available from: 2011-05-27 Created: 2011-05-19 Last updated: 2011-05-27Bibliographically approved
List of papers
1. 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, 195-204 p.Article 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 (ScopusID)
Note

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

Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2016-10-25Bibliographically approved
2. 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, 2899-2912 p.Article 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 (ScopusID)
Note

QC 20101029

Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2016-10-26Bibliographically approved
3. 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, 867-878 p.Article 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 (ScopusID)
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: 2011-09-29Bibliographically approved
4. Thermodynamics and Nucleation of m-Hydroxybenzoic Acid Polymorphs in Pure Solvents
Open this publication in new window or tab >>Thermodynamics and Nucleation of m-Hydroxybenzoic Acid Polymorphs in Pure Solvents
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:kth:diva-33834 (URN)
Available from: 2011-05-19 Created: 2011-05-19 Last updated: 2011-05-27Bibliographically approved
5. Influence of Solution Thermal and Structural History on the Nucleation of m-Hydroxybenzoic Acid Polymorphs
Open this publication in new window or tab >>Influence of Solution Thermal and Structural History on the Nucleation of m-Hydroxybenzoic Acid Polymorphs
2012 (English)In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 12, no 9, 4340-4348 p.Article in journal (Refereed) Published
Abstract [en]

The influence of solution pretreatment on primary nucleation of m-hydroxybenzoic acid has been investigated through 550 cooling crystallization experiments. The metastable zone width has been determined at constant cooling rate, and the time and temperature of the preceding superheating step have been varied. m-Hydroxybenzoic acid has two polymorphs, and the influence of the polymorph used to prepare the solutions has also been investigated. There is an overall tendency in the experiments for the solution to exhibit a larger metastable zone width if it is superheated for a longer time and at a higher temperature, but under the investigated conditions this tendency is not very strong. The results show that the metastable form II preferentially crystallizes in all experiments and in particular when the solution has been more strongly superheated for several hours. However, when the time and/or the temperature of superheating is reduced, there is an increasing tendency to obtain the stable form I. This is most clearly found for solutions prepared by dissolving form I. When the solutions are prepared by dissolution of form II, this tendency is weaker in what appears to be a systematic way. It is hypothesized that, unless the solution is strongly superheated for several hours, it will contain for a significant period of time clusters of solute molecules that can retain some degree of structure from the dissolved crystal. This leads to "memory" effects in the solution, which may influence subsequent nucleation. The work includes a comprehensive review of previous published work on the influence of thermal history on nucleation in solutions and melts.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
Keyword
Metastable Zone Width, Supersaturated Solutions, Cluster Formation, Crystallization, Crystals, Liquids
National Category
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-33835 (URN)10.1021/cg3000312 (DOI)000308279900009 ()2-s2.0-84865849344 (ScopusID)
Note

QC 20121123. Updated from manuscript to article in journal. QC 20161027 fulltext uploaded.

Available from: 2011-05-19 Created: 2011-05-19 Last updated: 2016-10-27Bibliographically approved
6. 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, 1631- p.Conference 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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