Issa, N. (2011) Towards more efficient screening of pharmaceutical cocrystals. Doctoral thesis, UCL (University College London).
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Pharmaceutical cocrystals are formed between active pharmaceutical ingredients (APIs) and coformers that are biologically safe. Cocrystals are of considerable relevance to the pharmaceutical industry as they offer the ability of optimizing the physical properties of an API whilst retaining its biological function. However, producing cocrystals is experimentally challenging and often results in undesired forms. The objective of work presented herein is to investigate a more effective screening approach. Assuming that the formation of cocrystals is thermodynamically driven, we tested whether a contemporary computational methodology can account for the formation of 26 known cocrystals. By comparing their calculated lattice energies with the sum of their components we found the majority of cocrystals to be thermodynamically more stable, implying that this computational method is sufficient and could be applied to the prediction of cocrystal formation. An experimental screening procedure for the formation of succinic acid and 4-aminobenzoic acid cocrystals was explored. Grinding and hot stage microscopy experiments provided a rapid indication of cocrystal formation. For systems showing an indication of cocrystal formation, more extensive screening was carried out using slow solvent evaporation with a diverse variety of solvents to grow single crystals for X-ray structural determination. The results produced 4 novel cocrystals. Finally a multistage computational process was used to generate lattice energy landscapes for succinic acid•2,2´-bipyridine and succinic acid•1,4-dicyanobenzene cocrystals and their components. Analysis of these landscapes rationalized why only one of these cocrystals had been formed in the experimental screening. This thesis shows that computational methods can be used as a complementary technique to experimental screening of cocrystals. The calculations could have been performed prior to the experimental work and so have the potential to narrow down experimental investigations to the most promising candidates.
|Title:||Towards more efficient screening of pharmaceutical cocrystals|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry|
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