De Novo

The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far

Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical

Five anhydrate polymorphs (forms I–V) and the isomorphic dehydrate (Hy_{dehy}) of dapsone (4,4′-diaminodiphenyl sulfone or DDS) were prepared and characterized in an interdisciplinary experimental and computational study, elucidating the kinetic and thermodynamic stabilities, solid form interrelationships, and structural features of the known forms I–IV, the novel polymorph form V, and Hy_{dehy}. Calorimetric measurements, solubility experiments, and lattice energy calculations revealed that form V is the thermodynamically stable polymorph from absolute zero to at least 90 °C. At higher temperatures, form II, and then form I, becomes the most stable DDS solid form. The computed 0 K stability order (lattice energy calculations) was confirmed with calorimetric measurements as follows, V (most stable) > III > Hy_{dehy} > II > I > IV (least stable). The discovery of form V was complicated by the fact that the metastable but kinetically stabilized form III shows a higher nucleation and growth rate. By combining laboratory powder X-ray diffraction data and ab initio calculations, the crystal structure of form V (P2_{1} /c, Z′ = 4) was solved, with a high energy DDS conformation allowing a denser packing and more stable intermolecular interactions, rationalizing the formation of a high Z′ structure. The structures of the forms I and IV, only observed from the melt and showing distinct packing features compared to the forms II, III, and V, were derived from the computed crystal energy landscapes. Dehydration modeling of the DDS hydrate led to the Hydehy structure. This study expands our understanding about the complex crystallization behavior of pharmaceuticals and highlights the big challenge in solid form screening, especially that there is no clear end point

Structure prediction of crystals, surfaces and nanoparticles

We review the current techniques used in the prediction of crystal structures and their surfaces and of the structures of nanoparticles. The main classes of search algorithm and energy function are summarized, and we discuss the growing role of methods based on machine learning. We illustrate the current status of the field with examples taken from metallic, inorganic and organic systems. This article is part of a discussion meeting issue 'Dynamic in situ microscopy relating structure and function'

The induction contribution to the lattice energy of organic crystals

A recently developed method for generating distributed, localized atomic polarizabilities from the ab initio molecular charge density is used to assess the importance of the induction energy in crystal structures of small organic molecules. Two models are first contrasted based on large cluster representing the crystalline environment: one using the polarizability model in which induced multipoles are evaluated in response to the electrostatic field due to atomic multipoles; the other is a complementary procedure in which the same cluster is represented by atomic point-charges and the molecular charge density is calculated ab initio in this environment. The comparable results of these two methods show that the contribution to the lattice energy from the induction term can differ significantly between polymorphic forms, for a selection of organic crystal structures including carbamazepine and oxalyl dihydrazide, and 3-azabicyclo[3,3,1]nonane-2,4-dione. The observed charge density polarization of naphthalene in the crystalline state is also reproduced. This demonstrates that explicit inclusion of the induction energy, rather than its absorption into an empirically fitted repulsion-dispersion potential, will improve the relative ordering of the lattice energies for computed structures, and that it needs to be included in crystal structure prediction. Hence, the distributed atomic polarizability model was coded into the lattice-energy minimization program DMACRYS (which was developed as a Fortran90 recoding of DMAREL) to allow the induction energy to be calculated

Structure prediction of crystals, surfaces and nanoparticles

We review the current techniques used in the prediction of crystal structures and their surfaces and of the structures of nanoparticles. The main classes of search algorithm and energy function are summarized, and we discuss the growing role of methods based on machine learning. We illustrate the current status of the field with examples taken from metallic, inorganic and organic systems. This article is part of a discussion meeting issue ‘Dynamic in situ microscopy relating structure and function’

Doctor of Philosophy

dissertationCrystal structure prediction is an important field of study, both for the development of new compounds and materials, and for the advancement of understanding crystallization processes. The Modified Genetic Algorithm for Crystal Structure Prediction, MGAC, is a software package for structure prediction that has had varying success in predicting the structures of many molecules. However, several advancements in the field of structure prediction have prompted a revision to the software, both from a scientific and technical standpoint. In this dissertation, the evaluation of a new method for energy calculation and structural optimization, dispersion corrected density functional theory, is presented, along with practical parameterizations for using density functional theory in crystal structure prediction. Next, a preliminary implementation of MGAC using density functional theory is outlined, including some key changes to the construction of unit cells, along with successful prediction results for the molecules glycine and histamine. Finally, a new implementation of MGAC is proposed to handle multiple space group prediction effectively, with accompanying preliminary prediction results for histamine using the new implementation of MGAC, called MGAC2

Calculation of the free energy of crystalline solids

The prediction of the packing of molecules into crystalline phases is a key step in understanding the properties of solids. Of particular interest is the phenomenon of polymorphism, which refers to the ability of one compound to form crystals with different structures, which have identical chemical properties, but whose physical properties may vary tremendously. Consequently the control of the polymorphic behavior of a compound is of scientific interest and also of immense industrial importance. Over the last decades there has been growing interest in the development of crystal structure prediction algorithms as a complement and guide to experimental screenings for polymorphs. The majority of existing crystal structure prediction methodologies is based on the minimization of the static lattice energy. Building on recent advances, such approaches have proved increasingly successful in identifying experimentally observed crystals of organic compounds. However, they do not always predict satisfactorily the relative stability among the many predicted structures they generate. This can partly be attributed to the fact that temperature effects are not accounted for in static calculations. Furthermore, existing approaches are not applicable to enantiotropic crystals, in which relative stability is a function of temperature. In this thesis, a method for the calculation of the free energy of crystals is developed with the aim to address these issues. To ensure reliable predictions, it is essential to adopt highly accurate molecular models and to carry out an exhaustive search for putative structures. In view of these requirements, the harmonic approximation in lattice dynamics offers a good balance between accuracy and efficiency. In the models adopted, the intra-molecular interactions are calculated using quantum mechanical techniques; the electrostatic inter-molecular interactions are modeled using an ab-initio derived multipole expansion; a semi-empirical potential is used for the repulsion/dispersion interactions. Rapidly convergent expressions for the calculation of the conditionally and poorly convergent series that arise in the electrostatic model are derived based on the Ewald summation method. Using the proposed approach, the phonon frequencies of argon are predicted successfully using a simple model. With a more detailed model, the effects of temperature on the predicted lattice energy landscapes of imidazole and tetracyanoethylene are investigated. The experimental structure of imidazole is Abstract | ii correctly predicted to be the most stable structure up to the melting point. The phase transition that has been reported between the two known polymorphs of tetracyanoethylene is also observed computationally. Furthermore, the predicted phonon frequencies of the monoclinic form of tetracyanoethylene are in good agreement with experimental data. The potential to extend the approach to predict the effect of temperature on crystal structure by minimizing the free energy is also investigated in the case of argon, with very encouraging results.Open Acces

Crystal structure prediction and thermodynamic modelling of chiral molecules

This thesis explores the potential of computed crystal energy landscapes as an aid in the rational design of chiral separation processes. Crystal structure prediction (CSP) methods have been used to explore the crystal energy landscapes of prototypical chiral systems and the corresponding lattice energies and properties are used to help explore the thermodynamics of these systems. The crystal energy landscape of two very different chiral systems is explored. The small, but very flexible 3-chloromandelic acid molecule which can form strong hydrogen bonding motifs, and the rigid lactide molecule where the crystal structures are dominated by weak van der Waals forces. These crystal energy landscapes highlight the complexity of chiral molecules, particularly the enantiopure structures which tend to be high Z’. These systems demonstrate that the factors which influences the kinetics of crystallisation and growth are not yet adequately understood. The accuracy of CSP methods was explored through the CCDC Blind Test on the supposedly rigid, pseudo-chiral structure XXII ([1,4]dithiino[2,3-c]isothiazole-3,5,6-tricarbonitrile). The crystal structure was successfully predicted within the submitted structures at a comparable rank to much more sophisticated prediction methods by other groups. This suggests that the CSP methods used in my research can give reliable results. The sublimation cycle is an approach which can be used to support the rational design of chiral separation process by crystallisation. Lattice energy calculations and k = 0 phonon calculations were performed for the 3-chloromandelic acid, lactide and naproxen experimental structures. These results have been used in conjunction with experimental methods, performed by experimentalists at the MPI, Magdeburg, to explore the sublimation cycle. The methods proposed show promise for aiding chiral separation process design

Isolation of enantiomers via diastereomer crystallisation

Enantiomer separation remains an important technique for obtaining optically active materials. Even though the enantiomers have identical physical properties, the difference in their biological activities make it important to separate them, in order to use single enantiomer products in the pharmaceutical and fine chemical industries. In this project, the separations of three pairs of diastereomer salts (Fig1) by crystallisation are studied, as examples of the ‘classical’ resolution of enantiomers via conversion to diastereomers. The lattice energies of these diastereomer compounds are calculated computationally (based on realistic potentials for the dominant electrostatic interactions and ab initio conformational energies). Then the experimental data are compared with the theoretical data to study the efficiency of the resolving agent. All three fractional crystallisations occurred relatively slowly, and appeared to be thermodynamically controlled. Separabilities by crystallisation have been compared with measured phase equilibrium data for the three systems studied. All crystallisations appear to be consistent with ternary phase diagrams. In the case of R = CH3, where the salt-solvent ternaries exhibited eutonic behaviour, the direction of isomeric enrichment changed abruptly on passing through the eutonic composition. In another example, R = OH, the ternaries indicated near-ideal solubility behaviour of the salt mixtures, and the separation by crystallisation again corresponded. Further, new polymorphic structures and generally better structure predictions have been obtained through out this study. In the case of R = CH3, an improved structure of the p-salt has been determined. In the case of R = C2H5, new polymorphic forms of the n-salts, II and III, have been both discovered and predicted. This work also demonstrates that chemically related organic molecules can exhibit different patterns of the relative energies of the theoretical low energy crystal structures, along with differences in the experimental polymorphic behaviour. This joint experimental and computational investigation provides a stringent test of the reliability of lattice modelling to explain the origins of chiral resolution via diastereomer formation. All the experimental and computational works investigated in this thesis are published (see APPENDIX 1)