Competition effects in cation binding to humic acid: Conditional affinity spectra for fixed total metal concentration conditions

Information on the Pb and Cd binding to a purified Aldrich Humic Acid (HA) is obtained from the influence of different fixed total metal concentrations on the acid- base titrations of this ligand. NICA (Non-Ideal Competitive Adsorption) isotherm has been used for a global quantitative description of the binding, which has then been interpreted by plotting the Conditional Affinity Spectra of the H+ binding at fixed total metal concentrations (CAScTM). This new physicochemical tool, here introduced, allows the interpretation of binding results in terms of distributions of proton binding energies. A large increase in the acidity of the phenolic sites as the total metal concentration increases, especially in presence of Pb, is revealed from the shift of the CAScTM towards lower affinities. The variance of the CAScTM distribution, which can be used as a direct measure of the heterogeneity, also shows a significant dependence on the total metal concentration. A discussion of the factors that influence the heterogeneity of the HA under the conditions of each experiment is provided, so that the smoothed pattern exhibited by the titration curves can be justified

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

Continuous crystallization of multicomponent materials

The challenges of developing continuous crystallization processes of multicomponent crystals are addressed within this thesis. Multicomponent crystals such as co-crystals and solid solutions, can be used to modify physical properties of active pharmaceuticals, agrochemicals and other materials. These can result in enhanced product properties such as higher solubility, faster dissolution, better stability or improved manufacturability in downstream processing through desirable morphology and better powder flowability. Continuous manufacturing is routinely used in many industries but is a new trend in the manufacture of pharmaceuticals driven by the potential to reduce plant footprint and intermediate inventory, improve yields, reduce lead time, implement real time monitoring and automation and make processes safer.Compared to crystallization of single component crystals, additional component and solid phases introduce additional complexity in the phase diagram. Co-crystal phase diagram measurement in a series of solvents can be very time consuming compared to a solubility curve of a single component. A semi-empirical approach of modeling phase diagrams as well as new methods of measuring phase diagrams of multicomponent materials are presented to accelerate the time to obtain a phase diagram compared to traditional approaches. Transitions from small scale batch crystallization to continuous crystallization is also demonstrated here for co-crystals and solid solutions with high selectivity and reproducibility with respect to the solid phase produced.The challenges of developing continuous crystallization processes of multicomponent crystals are addressed within this thesis. Multicomponent crystals such as co-crystals and solid solutions, can be used to modify physical properties of active pharmaceuticals, agrochemicals and other materials. These can result in enhanced product properties such as higher solubility, faster dissolution, better stability or improved manufacturability in downstream processing through desirable morphology and better powder flowability. Continuous manufacturing is routinely used in many industries but is a new trend in the manufacture of pharmaceuticals driven by the potential to reduce plant footprint and intermediate inventory, improve yields, reduce lead time, implement real time monitoring and automation and make processes safer.Compared to crystallization of single component crystals, additional component and solid phases introduce additional complexity in the phase diagram. Co-crystal phase diagram measurement in a series of solvents can be very time consuming compared to a solubility curve of a single component. A semi-empirical approach of modeling phase diagrams as well as new methods of measuring phase diagrams of multicomponent materials are presented to accelerate the time to obtain a phase diagram compared to traditional approaches. Transitions from small scale batch crystallization to continuous crystallization is also demonstrated here for co-crystals and solid solutions with high selectivity and reproducibility with respect to the solid phase produced

Outstanding Advantages, Current Drawbacks, and Significant Recent Developments in Mechanochemistry: A Perspective View

Although known since antiquity, mechanochemistry has remained dormant for centuries. Nowadays, mechanochemistry is a flourishing research field at the simultaneous stages of gathering data and (often astonishing) observations, and scientific argumentation toward their analysis, for which the combination of interdisciplinary expertise is necessary. Mechanochemistry’s implementation as a synthetic method is constantly increasing, although it remains far from being fully exploited, or understood on the basis of fundamental principles. This review starts by describing many remarkable advantages of mechanochemical reactions, simplifying and “greening” chemistry in solutions. This description is followed by an overview of the current main weaknesses to be addressed in the near future toward the systematic study of its energetics and chemical mechanisms. This review finishes by describing recent breakthrough experimental advances, such as in situ kinetics monitoring using synchrotron X-ray powder diffraction and Raman spectroscopy, plus equally significant computational chemistry approaches, such as quantum mechanochemistry, used for the understanding of covalent or hydrogen bond ruptures in biomolecules or mechanophores in polymers at the single-molecule level. Combined with new technologies to control temperature and pressure in ball mills, these appealing new methods are promising tools for establishing the fundamental knowledge necessary for the understanding of mechanochemical reactivity and mechanisms

PARALLEL POLYMER-BASED MICROEXTRACTION METHODS TO STUDY INTERMOLECULAR ASSOCIATION AND PHYSICOCHEMICAL PROPERTIES

Lipophilicity and acid dissociation constants are important physicochemical properties that in part determine the suitability of an organic molecule as a pharmacological agent. Intermolecular associations are omnipresent in chemical and biochemical systems and particularly important in the efficacy of an excipient for a poorly soluble drug. Current standard methods to determine lipophilicity require large amounts of pure sample and have problems due to emulsion formation. This dissertation describes a method based on distribution of the solutes between a polymer phase and an aqueous phase in a 96-well format, in the presence and absence of a receptor (e.g., candidate excipient) in one of the two phases. This parallel approach uses minimal amounts of organic solvent and only requires small amounts of sample. This approach has been used to determine polymer-water distribution coefficients of solutes. In addition, by measuring polymer-water distribution coefficients at a variety of experimental conditions, such as pH and receptor concentration, acid dissociation constants and solute-receptor binding constants have been successfully determined for several chemical systems. This method has been applied to measure binding constants of econazole with six cyclodextrins in aqueous solutions. The acid dissociation constant of econazole was determined by measuring econazole-cyclodextrin binding constants at various pH values. Distribution coefficients and acid dissociation constants of twenty-four novel drug-like compounds have also been determined by this parallel approach and compared to the values calculated by commercially available software. The software packages did not adequately predict experimental results, especially for ionizable compounds. This emphasizes the need for laboratory separations-based measurements of distribution coefficients. The polymeric phase was poly(vinyl chloride) (PVC) plasticized by 67% (w/w) dioctyl sebacate (DOS). Intermolecular association has also been studied in Teflon AF 2400, a fluorous polymer phase, with and without fluorous hydrogen bond donor Krytox 157 FSH in the 96-well approach. In addition, a novel fluorous receptor-doped fiber solid phase microextraction (SPME) was developed to selectively detect quinoline in aqueous solutions