No / Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium throughput approach, encompassing both a melt and solution crystallization step as a route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Kofler mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.

No / In this feature article we will focus on the issues relating to the crystal growth of co-crystals, with a particular emphasis on drug development. The initial focus of this perspective is on the relevant literature examples that may be able to inform our understanding with regards co-crystal crystallisation and the allied supramolecular concepts. The second part of this perspective contains selected examples from our own work, which add to the literature perspective. Topics include; nucleation templates, in situ synchrotron XRD studies, solid-state synthesis through mixing and screening strategies.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / The work presented in this thesis has demonstrated that supramolecular synthons can be used to make multicomponent crystals, and various synthons can be combined to make supermolecules. The synthons can also be used to construct nanoscale assemblies. Molecules containing single and multiple hydrogen-bond (HB) and halogen-bond (XB) acceptor sites have been synthesized in an effort to carry out supramolecular synthesis in order to establish a reliable hierarchy for intermolecular interactions. Pyrazole-based molecules have been made, combined with various carboxylic acids, and characterized using infrared (IR) spectroscopy to give a success rate of 55-70%. Reactions that gave a positive result were converted to solution experiments, and crystals were grown and characterized using single-crystal X-ray diffraction (XRD). The co-crystals display infinite 1-D chains with the intended stoichiometry and structural landscape on 6/6 occasions. The salts, on the other hand, display unpredictable stoichiometry and structural landscape on 5/5 occasions. Furthermore, the electrostatic charge on the primary hydrogen-bond acceptor, N(pyz), can be altered by adding a nitro, R-NO2, covalent handle to the backbone of the pyrazole molecule. Addition of a strongly electron withdrawing group significantly lowered the charge on the pyrazole nitrogen atom and, in turn, lowered the supramolecular yield to 10%. Ditopic molecules containing pyrazole and pyridine on the same molecular backbone were synthesized and characterized using 1H NMR. The molecules were co-crystallized with carboxylic acids, and the resulting solids were characterized using IR spectroscopy. The solids could then be classified as co-crystal or salt using specific markers in the IR spectrum. Single-crystal XRD was used to observe the intermolecular interactions in the co-crystals and salts, and the co-crystals were assigned to two groups: Group 1 (2) and Group 2 (2). The salts (4) show more unpredictability with stoichiometry and structural landscape. A library of ditopic molecules containing triazole and pyridine acceptor sites were synthesized and characterized using 1H and 13C NMR. The molecules were co-crystallized with carboxylic acids and the resulting solids were characterized using IR spectroscopy which demonstrated a 100% supramolecular yield whenever a pyridine moiety was present, consistent with results from Chapter 3. Single-crystal XRD was used to identify the intermolecular interactions in the co-crystals (2) and salt (1), and the results show that triazole can compete with pyridine for hydrogen bond donors. A library of ditopic molecules was also used for halogen-bonding (XB) studies with a series of activated iodine and bromine-based donors. The results show that iodine donors have a higher success rate range (12.5-75%) compared to bromine donors (16.7-50%) based on results obtained from IR spectra. Furthermore, the results from the XRD show that pyrazole nitrogen atoms can compete with pyridine for forming XB, and two groups of supramolecular synthons were observed. Finally, relatively weak non-covalent interactions, HB and XB, can influence the assembly of nanoparticles based on IR spectroscopy and TEM images. The assembly of the particles is influenced by specific capping ligands, which were synthesized and characterized using 1H, 13C and 19F NMR. The results demonstrate that relatively weak non-covalent interactions based on HB and XB interactions can influence nanoparticle assembly.

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Various aspects of the surface chemistry of a ruthenium (1010) single crystal have been investigated under ultra-high vacuum conditions, employing the techniques of Auger Electron Spectroscopy, Low Energy Electron Diffraction, Multimass Thermal Desorption Spectroscopy, photoemission spectroscopies and work function measurements. The studies were undertaken with a view towards the applicability of ruthenium and iron-ruthenium alloys to the ammonia synthesis, though work relevant to the Fischer-Tropsch synthesis was also performed. The interactions of the gases nitrogen, hydrogen and ammonia with the clean surface were all explored. Molecular nitrogen was found to have an extremely low sticking probability of less than 10<SUP>-9</SUP> at room temperature, but surface nitrogen atoms were deposited via two separate means, using either a mixture of nitrogen ions or nitrogen atoms themselves as the impinging species. Both chemisorbed and bulk implanted states were thereby observed. Hydrogen uptake at 310 K saturated at small doses but an estimate of 256 kJ mol<SUP>-1</SUP> was made for the Ru-H bond strength from thermal desorption traces. Ammonia readily adsorbed at and above room temperature. Partial dissociation occurred at 300 K, the extent of fragmentation increasing as the crystal temperature was raised. Strong electron beam perturbations of the adlayer occurred, accelerating the rate of adsorption and resulting in the appearance of otherwise unobservable LEED patterns. The behaviour of the model promoter potassium was relatively typical of alkali metal/transition metal systems, though the anisotropic substrate potential was found to induce a series of interesting one dimensionally incoherent compressed overlayer structures. A further striking observation was the occurrence of substantial bulk dissolution of potassium following small doses at 430 K. The promoting effects of potassium on CO adsorption were investigated and interpreted interms of a recent modification of the Blyholder model, which combines indirect, through metal and direct, through space interactions. Finally, the deposition of iron on Ru(10bar 10) was studied. At 300 K the iron film grew in a metastable layer by layer mode, which rapidly rearranged on heating to either an alloy phase or a regime of 3D crystallites lying above one or two iron monolayers. Adsorption at elevated temperatures produced essentially the same results as heating layers deposited at room temperature.

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