A polymorphic substance is capable of forming a number of different crystalline phases that are referred to as its polymorphs. The critical process that determines the outcome of a crystallization process in a polymorphic system is thought to be the nucleation state, which is the self-assembled stage just prior to the formation of crystals with long-range order. While nucleation is well known to be influenced by macroscopically measurable parameters such as temperature, supersaturation and solvent choice our understanding of the underlying molecular self-assembly processes is very limited. The research described in this thesis explores a new approach to extending our knowledge in this area by the use of a combination of medium throughput crystallisation experiments together with the computation of a range of molecular and solute/solvent descriptors of the system under study.The main objective of the work was to develop a protocol for relating experimental and computational data via artificial neural network (ANN) analysis, to identify significant links between experimental polymorphic outcomes and molecular properties. By creating a model that can predict the polymorphic form in a given experiment it is anticipated that our understanding of links between nucleation and crystallisation will be enhanced through the determining the pivotal properties of a molecule that cause it to form one polymorph over another. The ANN method was developed in the context of the carbamazepine system, applying several statistical techniques to the results of 88 crystallisation experiments, featuring 13 solvents, 3 evaporation rates and 4 temperatures. The results show that this approach allows the formulation of further research hypotheses through examination of the physical meaning of the set of descriptors identified by the ANN approach. Crucially, principal component analysis (PCA) was found to be able to efficiently narrow down large sets of computationally derived descriptors to a manageable set by removing redundancy through strongly cross-correlated parameters. The best ANN model generated in this research was capable of predicting the major polymorphic form in 89 % of cross-validation experiments.The optimised set of descriptors included both solute and solvent properties, which predominantly described the intermolecular interactions in solution. The physical meanings of the descriptors and their impact on the molecular processes during nucleation has been considered and their cross correlation has been examined. Initial results from further experimentation with the tolbutamide and ROY systems indicate that the methodology is also transferable to other polymorphic systems.

This thesis describes the use of chiral counter-ions for the enantiomeric separation of amines in non-aqueous capillary electrophoresis. The investigations have been concentrated on studies of the influence, of the chiral counter-ion, the solvent, the electrolyte and the analyte, on the enantioselective separation. Modified divalent dipeptides have been introduced in capillary electrophoresis for the separation of amino alcohols and chiral resolution of amines. Association constants for the ion-pair between dipeptide and amino alcohol could be utilized for development of separation systems with higher amino alcohol selectivity. Chiral discrimination (ion-pair formation) between the dipeptides and amines are preferably generated in non-aqueous background electrolytes (BGEs). The amount of triethylamine in the BGE determined the dipeptide charge and a divalent dipeptide promoted higher enantioselectivity than a monovalent dipeptide. An N-terminal-end blocking group and glutamic acid at the C-terminal-end of the dipeptide was important for chiral separation of the amines. Chemometric and univariate methods have been employed for evaluation of suitable solvent compositions in the BGE. An experimental design including a single solvent as well as binary, ternary and quaternary mixtures of polar organic solvents, showed that optimal enantioresolution was obtained with an ethanol:methanol 80:20 mixture in the BGE.  Furthermore, water was found to have an adverse influence on enantioselectivity and no enantioresolution was obtained with BGEs containing more than 30 % water. An alkali metal hydroxide added to the BGE affected the chiral separation by competing ion-pair formation with the selector. The electroosmosis was reduced in order of decreasing alkali metal ion solvated radius and became anodic using K, Rb or Cs in ethanolic BGEs. The correlation between the amino alcohol structure and the enantioselectivity was investigated using chemometrics. The obtained models showed that enantioselectivity for the amino alcohols was promoted by e.g. degree of substitution and substituent size on the nitrogen.

<p>Capillary Electrophoresis (CE) was explored as a means for physicochemical and biopharmaceutical characterisation of small drug molecules. Special attention was paid to the characterisation of acid-base and lipophilic properties of drug compounds by analysing their migration behaviour in different CE systems. The thesis comprises an overview of the field together with separate studies on the different topics.</p><p>The utility of CE for the determination of pK_a of labile drug compounds was investigated. A general methodology was developed comprising key steps such as the use of a stabilising sample diluent, electromigration injection, and analyte characterisation by UV-Vis spectroscopy. The methodology was successfully applied for two sets of drug compounds, labile at low and high pH, respectively.</p><p>CE was also evaluated for experimental modelling of passive intestinal membrane permeability by studying analyte migration in liposomal, microemulsion and micellar electrolytes. Good correlation is reported between CE migration and Caco-2 cell absorption estimates and for in vitro inhibition of thrombin. Interestingly, a slightly better correlation was obtained for liposomal electrolytes.</p><p>The utility of liposomes in CE was further extended by developing a novel procedure for immobilising liposomes inside fused silica capillaries. This approach enabled direct on-line coupling of liposome CE to high sensitivity mass spectrometry. The utility of liposome-coated capillaries is demonstrated for estimating drug passive intestinal membrane permeability. Its use in biopharmaceutical drug profiling is discussed.</p><p>Utilising advanced molecular descriptors, commonly applied to in silico prediction of passive intestinal membrane permeability, migration of analytes in micellar CE systems could be well predicted. The novel approach was based on hierarchical multivariate analytics and use of molecular descriptors for both analytes and micellar media surfactants. Demonstrated results propose that the CE format could be useful to validate how representative molecular descriptors are for describing molecular behaviour in complex liquid media, e.g. physiological systems.</p>

Capillary Electrophoresis (CE) was explored as a means for physicochemical and biopharmaceutical characterisation of small drug molecules. Special attention was paid to the characterisation of acid-base and lipophilic properties of drug compounds by analysing their migration behaviour in different CE systems. The thesis comprises an overview of the field together with separate studies on the different topics. The utility of CE for the determination of pKa of labile drug compounds was investigated. A general methodology was developed comprising key steps such as the use of a stabilising sample diluent, electromigration injection, and analyte characterisation by UV-Vis spectroscopy. The methodology was successfully applied for two sets of drug compounds, labile at low and high pH, respectively. CE was also evaluated for experimental modelling of passive intestinal membrane permeability by studying analyte migration in liposomal, microemulsion and micellar electrolytes. Good correlation is reported between CE migration and Caco-2 cell absorption estimates and for in vitro inhibition of thrombin. Interestingly, a slightly better correlation was obtained for liposomal electrolytes. The utility of liposomes in CE was further extended by developing a novel procedure for immobilising liposomes inside fused silica capillaries. This approach enabled direct on-line coupling of liposome CE to high sensitivity mass spectrometry. The utility of liposome-coated capillaries is demonstrated for estimating drug passive intestinal membrane permeability. Its use in biopharmaceutical drug profiling is discussed. Utilising advanced molecular descriptors, commonly applied to in silico prediction of passive intestinal membrane permeability, migration of analytes in micellar CE systems could be well predicted. The novel approach was based on hierarchical multivariate analytics and use of molecular descriptors for both analytes and micellar media surfactants. Demonstrated results propose that the CE format could be useful to validate how representative molecular descriptors are for describing molecular behaviour in complex liquid media, e.g. physiological systems.