Monte Carlo algorithm based on internal bridging moves for the atomistic simulation of thiophene oligomers and polymers

We introduce a powerful Monte Carlo (MC) algorithm for the atomistic simulation of bulk models of oligo- and poly-thiophenes by redesigning MC moves originally developed for considerably simpler polymer structures and architectures, such as linear and branched polyethylene, to account for the ring structure of the thiophene monomer. Elementary MC moves implemented include bias reptation of an end thiophene ring, flip of an internal thiophene ring, rotation of an end thiophene ring, concerted rotation of three thiophene rings, rigid translation of an entire molecule, rotation of an entire molecule and volume fluctuation. In the implementation of all moves we assume that thiophene ring atoms remain rigid and strictly co-planar; on the other hand, inter-ring torsion and bond bending angles remain fully flexible subject to suitable potential energy functions. Test simulations with the new algorithm of an important thiophene oligomer, {\alpha}-sexithiophene ({\alpha}-6T), at a high enough temperature (above its isotropic-to-nematic phase transition) using a new united atom model specifically developed for the purpose of this work provide predictions for the volumetric, conformational and structural properties that are remarkably close to those obtained from detailed atomistic Molecular Dynamics (MD) simulations using an all-atom model. The new algorithm is particularly promising for exploring the rich (and largely unexplored) phase behavior and nanoscale ordering of very long (also more complex) thiophene-based polymers which cannot be addressed by conventional MD methods due to the extremely long relaxation times characterizing chain dynamics in these systems

Structural investigations with high pressure techniques and multicomponent systems

This thesis illustrates the use of high pressure crystallography techniques for the discovery and investigation of solid-state forms and probes the relationship between molecular structure and compression of both single and multicomponent systems. As well as investigating a data-driven approach to directing experimental co-crystallisation attempts.;Single crystal X-ray diffraction techniques are a highlight in all areas of this study, as well as computational approaches which were used in the evaluation of the interactions of small molecule systems. Data-mining of the Cambridge Structural Database made the comparison of the compression studies richer.;The pharmaceutical co-crystal, indomethacin and saccharin was analysed with respect to increasing pressure. The system is an example of a homomolecular synthon co-crystal allowing investigation of the component dimers free of strong interaction with surrounding molecules. The ambient pressure structure remains stable but investigation showed that the saccharin dimer sits in a pocket made by indomethacin allowing the dimer to lie further apart than in the pure compound.;To follow, a structural compression study of the single component saccharin using synchrotron radiation lead to the structural characterisation of the first new polymorph of saccharin. The hydrogen bonding pattern of the new phase remains consistent however Pixel calculations revealed that the biggest difference in packing arises due to the reduction of an interlayer distance.;To further explore multicomponent systems, two stoichiometric ratios of benzoic acid and isonicotinamide (2:1 & 1:1) were investigated. The rate of compression in these systems are almost identical despite the different molecular packing in each of the stoichiometric ratios. Through the investigation of materials in these initial chapters, the rate of compression in particular supramolecular synthons, e.g. amide-dimers, is demonstrated to be consistent despite the difference in the molecular make-up of the materials under study and their packing arrangements.;Lastly, a data-driven approach was applied in directing the discovery of a new solid-state entity. Following previous failed attempts, machine learning was employed to direct experimental co-crystallisations which led to a new co-crystal of Artemisinin and 1-Napthol. Pixel calculations revealed that the largest contribution to crystal stabilisation comes from dispersion energy and enabled the identification of dominant intermolecular interactions in the crystal structures.This thesis illustrates the use of high pressure crystallography techniques for the discovery and investigation of solid-state forms and probes the relationship between molecular structure and compression of both single and multicomponent systems. As well as investigating a data-driven approach to directing experimental co-crystallisation attempts.;Single crystal X-ray diffraction techniques are a highlight in all areas of this study, as well as computational approaches which were used in the evaluation of the interactions of small molecule systems. Data-mining of the Cambridge Structural Database made the comparison of the compression studies richer.;The pharmaceutical co-crystal, indomethacin and saccharin was analysed with respect to increasing pressure. The system is an example of a homomolecular synthon co-crystal allowing investigation of the component dimers free of strong interaction with surrounding molecules. The ambient pressure structure remains stable but investigation showed that the saccharin dimer sits in a pocket made by indomethacin allowing the dimer to lie further apart than in the pure compound.;To follow, a structural compression study of the single component saccharin using synchrotron radiation lead to the structural characterisation of the first new polymorph of saccharin. The hydrogen bonding pattern of the new phase remains consistent however Pixel calculations revealed that the biggest difference in packing arises due to the reduction of an interlayer distance.;To further explore multicomponent systems, two stoichiometric ratios of benzoic acid and isonicotinamide (2:1 & 1:1) were investigated. The rate of compression in these systems are almost identical despite the different molecular packing in each of the stoichiometric ratios. Through the investigation of materials in these initial chapters, the rate of compression in particular supramolecular synthons, e.g. amide-dimers, is demonstrated to be consistent despite the difference in the molecular make-up of the materials under study and their packing arrangements.;Lastly, a data-driven approach was applied in directing the discovery of a new solid-state entity. Following previous failed attempts, machine learning was employed to direct experimental co-crystallisations which led to a new co-crystal of Artemisinin and 1-Napthol. Pixel calculations revealed that the largest contribution to crystal stabilisation comes from dispersion energy and enabled the identification of dominant intermolecular interactions in the crystal structures

Molecular Flexibility in Crystal Structure Prediction

The packing of molecules in solids greatly affects the properties of the bulk materials. This is particularly important for the pharmaceutical industry, where the discovery of crystal forms at a late stage of process development can have disastrous consequences. As a result, the importance of polymorphism in crystal structures of organic molecules has been recognised for many years. This thesis presents computational developments that can complement experimental form screening of molecules for which conformational flexibility is significant. Current methods for crystal structure prediction are limited by the extent of molecular flexibility that can be practically handled due to the prohibitive computational cost associated with quantum mechanical calculations integrated in most of the successful approaches. In order to reduce the number of quantum mechanical evaluations, local approximate models can be defined for the estimation of the intramolecular energy, molecular geometry and the conformationally dependent intermolecular electrostatic model. A novel algorithm, CrystalOptimizer, for the accurate local minimisation of the lattice energy of crystals involving flexible organic molecules is presented. The main novelty of the algorithm is the use of dynamically constructed and updated local approximate models which essentially make available the full accuracy of quantum mechanical models at each and every iteration of the minimisation algorithm, requiring only a small number of explicit quantum mechanical calculations. This has made possible the accurate treatment of molecules involving a relatively large numbers of atoms with significant flexibility in torsional and bond angles and even bond lengths. The performance of the algorithm is critically assessed and demonstrated on a set of single and multi-component crystals. An extension of an existing algorithm for the identification of low energy crystal structures of flexible molecules, CrystalPredictor, is also described. In the proposed modification, the intramolecular energy and the molecular conformation are modelled using local approximate models. This provides a more realistic model for the effects of the flexible degrees of freedom on the molecular geometry and lattice energy. The use of deterministic low-discrepancy sequences ensures an extensive and uniform coverage of the multivariable search space. A parallelised implementation of the algorithm allows minimisations from several hundreds of thousands of initial guesses to be carried out in reasonable time. A further computational benefit is derived by the storage of the information used to construct the local approximate models in databases, which can be re-used in subsequent re-minimisation of structures with more accurate models for the lattice energy. The usefulness of these modifications is demonstrated on the ROY molecule, for which the structures of all experimentally known polymorphs are identified by the algorithm. By combining the above algorithms, a comprehensive multi-stage methodology for ab initio determination of the crystal structure of a given molecule based solely on its atomic connectivity is presented. The application of the methodology to two large and flexible molecules of pharmaceutical interest is also demonstrated

Nucleation and growth of pharmaceutical crystals

Investigating nucleation, crystal growth and solid-state transformations at the nanoscale are of significant interest, as more complex routes have roused questions about the classical view of these processes. This thesis reports the characterisation of prenucleation clusters in olanzapine (OZPN) aqueous solutions, their role in non-classical heteronucleation of OZPN hydrates and during crystal growth mechanism.;Atomic force microscopy studies of the (100)OZPNI face of OZPN I crystals in contact with water show the formation, growth, and order of dense nanodroplets leading to crystallization of OZPN dihydrate on the surface of OZPN I. Dihydrate polymorphic form is driven by a templating effect of the underlying OZPN I lattice. The size and volume fraction of nanodroplets in purely aqueous and mixed ethanol and water OZPN solutions show that their radius is steady in time at ca. 35 nm and it is independent of the OZPN concentration and the solvent composition.;The OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviours are consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. Although the presence of prenucleation clusters is critical during OZPN phase transformation, it was observed that clusters do not take part in a growth mechanism and OZPN layers are generated by a spiral growth. Step velocity shows a nonlinear dependence on OZPN concentration.;The proposed growth model suggests that OZPN layers propagate by incorporation of OZPN dimers present as a minor species in OZPN solution. The growth by dimers is faster not owing to spatial or entropic factors or weakly bound solvent, but to the accumulation of dimers on crystal surfaces due to stronger binding. These findings provide guidance towards enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems.Investigating nucleation, crystal growth and solid-state transformations at the nanoscale are of significant interest, as more complex routes have roused questions about the classical view of these processes. This thesis reports the characterisation of prenucleation clusters in olanzapine (OZPN) aqueous solutions, their role in non-classical heteronucleation of OZPN hydrates and during crystal growth mechanism.;Atomic force microscopy studies of the (100)OZPNI face of OZPN I crystals in contact with water show the formation, growth, and order of dense nanodroplets leading to crystallization of OZPN dihydrate on the surface of OZPN I. Dihydrate polymorphic form is driven by a templating effect of the underlying OZPN I lattice. The size and volume fraction of nanodroplets in purely aqueous and mixed ethanol and water OZPN solutions show that their radius is steady in time at ca. 35 nm and it is independent of the OZPN concentration and the solvent composition.;The OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviours are consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. Although the presence of prenucleation clusters is critical during OZPN phase transformation, it was observed that clusters do not take part in a growth mechanism and OZPN layers are generated by a spiral growth. Step velocity shows a nonlinear dependence on OZPN concentration.;The proposed growth model suggests that OZPN layers propagate by incorporation of OZPN dimers present as a minor species in OZPN solution. The growth by dimers is faster not owing to spatial or entropic factors or weakly bound solvent, but to the accumulation of dimers on crystal surfaces due to stronger binding. These findings provide guidance towards enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems