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)

Pharmaceutical Co-crystals; Screening Optimisation, Utility and Performance

Co-crystallisation is currently a ‘hot topic’ in pharmaceutical development among other fields. Modification of the physicochemical properties of the parent material by inclusion of a second component within the crystal structure, with the potential to lead to large improvements in useful attributes, being the key reason for the interest in co-crystals. Being able to efficiently utilise co-crystallisation to ameliorate problem properties of drugs or other compounds would be a boon to many industries, the pharmaceutical being an ideal example. Limitations in current ability to predict co-crystal formation and potential property modification presents a great opportunity for development in this research area. The work presented in this thesis encompasses the optimisation of a high-throughput ultrasonication based physical co-crystal screen paired with a computational pre-screen, the application of this optimised screen and the analysis of both co-crystalline and co-amorphous materials resulting from the screening. An initial optimisation of a manual physical co-crystal screen was later transferred to an automated screen implemented on a robotics platform. The implementation of the screen and subsequent analysis of products led to the discovery of the stabilisation of an amorphous form of highly polymorphic compound, ROY, through a predicted co-former interaction. The interactions responsible for the stabilisation were further investigated in the ROY:pyrogallol co-amorphous material and it was found that certain analogues of pyrogallol exhibit the same behaviour with ROY depending on the presence and position of specific functionality. Implementation of the optimised co-crystal screen to the antiprotozoal drug ornidazole led to the detection of 23 hits and the crystal structure of the 1:1 co-crystal of ornidazole and 5nitroisophthalic acid being determined by single crystal X-ray diffraction. Characterisation of this co-crystal found that it crystallised much more readily than pure ornidazole, potentially improving its processing characteristics, but that unexpectedly had a lower intrinsic dissolution rate than either of the parent components. In comparison, formulation and characterisation of the already known zafirlukast:piperazine co-crystals showed that large improvements in dissolution rates and oral bioavailability in relation to the parent drug are possible. Specifically, the 1:1 zafirlukast:piperazine co-crystal showed a large increase in dissolution rate in vitro and an accompanying six-fold increase in in vivo oral bioavailability

The formation, properties and impact of secondary organic aerosol: current and emerging issues

Secondary organic aerosol (SOA) accounts for a significant fraction of ambient tropospheric aerosol and a detailed knowledge of the formation, properties and transformation of SOA is therefore required to evaluate its impact on atmospheric processes, climate and human health. The chemical and physical processes associated with SOA formation are complex and varied, and, despite considerable progress in recent years, a quantitative and predictive understanding of SOA formation does not exist and therefore represents a major research challenge in atmospheric science. This review begins with an update on the current state of knowledge on the global SOA budget and is followed by an overview of the atmospheric degradation mechanisms for SOA precursors, gas-particle partitioning theory and the analytical techniques used to determine the chemical composition of SOA. A survey of recent laboratory, field and modeling studies is also presented. The following topical and emerging issues are highlighted and discussed in detail: molecular characterization of biogenic SOA constituents, condensed phase reactions and oligomerization, the interaction of atmospheric organic components with sulfuric acid, the chemical and photochemical processing of organics in the atmospheric aqueous phase, aerosol formation from real plant emissions, interaction of atmospheric organic components with water, thermodynamics and mixtures in atmospheric models. Finally, the major challenges ahead in laboratory, field and modeling studies of SOA are discussed and recommendations for future research directions are proposed

Exploring and anticipating supramolecular synthons: from fundamental science to practical applications

Doctor of PhilosophyDepartment of ChemistryChrister B. AakeröyFour different methods; molecular electrostatic potentials (MEPs), hydrogen-bond energies (HBE), hydrogen-bond propensities (HBP) and hydrogen-bond coordination (HBC) were used for mapping out the structural landscape of twelve pyrazole and twelve thiazole based molecules. In seven out of eight crystal structures obtained in pyrazoles, a combination of HBE and HBP predicted the experimentally observed synthons correctly. In all eight crystal structures obtained in thiazoles, the synthons were predicted correctly using all four methods. A series of co-crystallizations between twelve pyrazole with twenty carboxylic acids (240 experiments), and twelve thiazole with twenty carboxylic acids (240 experiments) were carried out to build an experimental library that could be used for evaluating the ability of electrostatics, energies, propensities and molecular complementarity methods to rationalize the observed intermolecular interactions. The results suggested that a combination of electrostatics and molecular complementarity are essential for identifying the predominant molecular recognition events in the pyrazole based study, and methods such as MEPs, HBE, and HBP all predicted the observed synthons in co-crystals of the thiazole-based molecules. In order to examine competition between hydrogen and halogen bonds, and to synthesize ternary co-crystals, four thiazole based molecules were co-crystallized with 15 hydrogen-bond donors and one halogen bond donor resulting in new co-crystals in 44 out of 60 experiments, and the crystal structures of two ternary co-crystals were obtained. A series of eight unactivated and activated amide functionalized molecules were synthesized to establish a supramolecular halogen-bond hierarchy. The positive electrostatic potential on the halogen atoms was enhanced through an sp-hybridized carbon and electron-withdrawing fluoro group(s) next to amide group. Tetraflourinated and iodoethynyl based molecules were identified as the most effective halogen-bond donors and were therefore least successful for co-crystal synthesis. In order to predict crystallizability of 83 drug-like molecules a molecule, logistic regression approach was employed using molecular descriptors such as molecular weight, rotatable bond, surface area, heteroatom, melting temperature, glass transition temperature, and molecular shape/volume. Four different models were developed, and the success rate was above 85% (using experimental DSC data for the crystallization classification). Finally, the solid-form landscape of urea was explored using full interaction maps (FIMs), and data from the CSD to develop optimum protocols for synthesizing co-crystals of this compound. As a result, 49 of 60 attempted reactions produced new co-crystals. Moreover, the goal of reducing solubility and lowering hygroscopicity of the parent compound was achieved, which, in turn, offers new opportunities for a slow-release fertilizer with limited hygroscopicity thereby reducing many current problems of transport, handling, and storage of urea

Survey of methodologies of pharmaceutical interest for quantification of crystal form via X-Ray Powder Diffraction

The interest on polymorphism of arises from their different properties. A strategy to improve the properties of compound, is the formation of cocrystal. In this PhD project, cocrystal statistical analysis and experimental screening of allantoin and some coformers were performed. No cocrystal was obtained, experimental results disagree with the statistical analysis. Quantitative method of crystalline forms via X-Ray Powder Diffraction are extremely interesting for pharmaceutical companies. In the thesis real cases with different approaches of quantitative analysis are reported. I presented the quantification of paracetamol form II impurity in Tachifludec containing paracetamol form I using univariate method in which the main issue is the identification of a specific peak. The presence of several peaks in the formulation was overcome by applying the standard addition method spiking the formulation with form II. Univariate and multivariate method NAS were compared, and the best results were obtained with the application of the multivariate method. These approaches were also evaluated in the case of mixture amorphous-crystalline. Furthermore, it was studied the potential use of stable amorphous surrogate instead to the unstable real amorphous. Even in these cases, multivariate method achieved the best results. The novel quantification method Direct derivation (DD) based on intensity–composition equation was applied to determine crystallinity of mixture amorphous-crystalline. The quantification method was evaluated in three scenarios: method a) with unit cell parameters, method b) structural information is unknown, and method c) only the mixtures’ patterns are available. Method a and b achieved more accurate results because of better description of the crystalline phase. Method b was evaluated in sample covered by containment system as the Kapton® film to evaluate the analysis of highly potent compounds. The DD method has been revealed the best method to estimate the crystallinity degree of formulation containing highly potent compound deposited on catheter balloon

Mechanistic Understanding of Co-crystal solubility and dissolution by using a combination of Experimental and Molecular Modelling Techniques

The purpose of this study is to improve the solubility, dissolution rate and permeability of poorly water-soluble drugs by understanding the mechanism of dissolution at molecular level of Flufenamic acid and Carbamazepine co-crystals in the presence of polymers. This study has been separated into four sections: (1) Formation of pharmaceutical co-crystals: Three pharmaceutical co-crystals of poorly water soluble active pharmaceutical ingredient (API) of Flufenamic acid (FFA) and Carbamazepine (CBZ) were synthesized, including 1:1 Flufenamic acid-theophylline co-crystal (FFATP CO), 1:1 Flufenamic acid-nicotinamide co-crystal (FFA-NIC CO) and 1:1 Carbamazepine-nicotinamide co-crystal (CBZ-NIC CO). The results of Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray Powder Diffraction (XRPD) confirmed the formation of co-crystals. (2) The effect of polymers on the surface dissolution of co-crystals: The influence of three polymers (polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2- pyrrolidone (60%) and vinyl acetate (40%) (PVP-VA)) on the surfaces of FFA-TP CO, FFA-NIC CO and CBZ-NIC CO was studied using Atomic force Microscopy (AFM), Scanning electron microscopy (SEM) and Raman spectroscopy. It was found that the co-crystals have different dissolution mechanisms, and that addition of polymers can alter the dissolution properties of co-crystals by interacting with the crystal faces. (3) The molecular interactions between the drugs, co-formers and polymers were investigated using Nuclear Magnetic Resonance (NMR) and Diffusion Ordered Spectroscopy (DOSY). It was found that the type of a polymer, its concentration, and the interaction of the polymer with a co-former in solution will significantly affect the FFA and CBZ co-crystals (4). Molecular modelling of free drug molecules with coformers and polymers in the presence of water molecules: Results indicate bulk precipitation could be occurring for FFA molecules in solution and that PVP-VA was an effective precipitation inhibitor for all three co-crystals studied in solution. Overall, PVP was an effective polymer for surface precipitation inhibitor and PVP-VA was the most effective inhibitor for precipitation in solution

In silico ligand fitting/docking, computational analysis and biochemical/biophysical validation for protein-RNA recognition and for rational drug design in diseases

Kaposi’s sarcoma-associated herpesvirus, is a double-stranded DNA γ - herpesvirus and the main causative agent of Kaposi’s sarcoma (KS). γ - herpesviruses undergo both lytic and latent replication cycles; and encode proteins that modulate host transcription at the RNA level, by inducing decay of certain mRNAs. Here we describe a mechanism that allows the viral endo-/exonuclease SOX to recognise mRNA targets on the basis of an RNA motif and fold. To induce rapid RNA degradation by subverting the main host mRNA degradation pathway SOX was shown to directly bind Xrn1. This may shed light as to how some viruses evade the host antiviral response and how mRNA degradation processes in the eukaryotic cell are involves in this