Crystal growth and design of multicomponent pharmaceuticals

Abstract

Cocrystallisation and salt formation is a widely studied method of optimising the action of Active Pharmaceutical Ingredients (APIs) without chemical modification of the parent compound. Careful selection of suitable coformers can lead to enhancement of both the bioavailability and mechanical handling properties of APIs. Bioavailability is the rate and extent of the absorption of an API from a drug product to become available at the desired active site. Modulation of intermolecular bonding can alter the overall bioavailability by adjusting crystal lattice energies, in turn modulating properties such as solubility, dissolution rate and stability. The crystal shape and size can also have a large effect on the final formulation properties of API’s, with equant block shapes largely being preferable. Needle like shaped crystals can pose problems during manufacturing as suspensions of needles are difficult to filter and breakages lead to fines generation causing blockages in manufacturing equipment. On a laboratory scale needle shaped crystals are undesired due to poor X-Ray diffraction characteristics. Needle morphologies also often exhibit poor dissolution and solubility characteristics. Intermolecular bonding modification through cocrystallisation can give more desirable morphologies with the use of additives to stunt growth in certain bonding directions also been shown to be effective. The aim of this thesis was thus to design multicomponent systems of pharmaceuticals, to develop a novel method for their manufacture through the use of gas phase crystal growth and to investigate the formation of needle-like crystals. Firstly, a comprehensive study of salt formation of fluoroquinolones with ,-dicarboxylic acids was carried out. Fluoroquinolones are widely prescribed broad-spectrum antibiotics whose therapeutic efficacy suffers from their low solubility in aqueous media. The effect of coformer spacer length on crystal packing was studied to investigate the impact on solubility of the fluoroquinolones. Evaluation of solubility effects were hindered during this study due to persistent solvate formation. Thus in this thesis a method was developed for the growth of multicomponent crystals from the gas phase through the use of co-sublimation. Using the developed multi-zone heating method in vacuo, it was shown to be possible to prepare multicomponent single crystals within hours, focusing on the growth of diflunisal, a non-steroidal anti-inflammatory drug (NSAID). Growth of multicomponent crystals of diflunisal from the solution phase has proved difficult due to solvate formation and highly anisotropic growth behaviour. In addition, tailor made additives were shown to have the ability to dramatically control the morphology of diflunisal cocrystals produced from the gas phase, enabling the formation of more equant blocks from needle forms. Salt formation was observed during gas phase crystal growth in several cases. To investigate the formation of these salts DFT studies were carried out and found that the environment around a pair of molecules in a prenucleation cluster can emulate solvation effects, allowing proton transfer after condensation in these clusters. Going further, the formation of ternary multicomponent crystals was studied with the anti parasitic, pyrimethamine. Ternary crystallization can provide a further avenue for the enhancement of API properties but has however been little studied compared to binary mixtures due to the difficulty in producing such systems. Pyrimethamine was chosen as a model compound to study ternary formation due to the presence of a donor-acceptor-donor (DAD) and donor-acceptor (DA) binding sites. The formation of ternary systems was studied through the use of solution, mechanochemical and gas phase crystal growth, with the multi zone heating method shown to be able to produce ternary crystalline systems with careful control of the sublimation rates. Lastly, the growth of persistent needle formers was studied to determine the factors leading to needle-like crystal growth through the analyses of intermolecular interactions and crystal packing. It was shown that crystalline structures with a 1D growth motif possessing an interaction energy > −30 kJ/mol with at least 50% vdW contact motif neighbours and a filled monolayer unit cell will persistently form needles from all solvents, however if lacking some of these characteristics then morphology can be controlled through the choice of solvent.