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Title: Drug-cyclodextrin complexes : an approach to enhance the solubility and dissolution properties of poorly soluble drugs
Author: Rudrangi, Shashi Ravi Suman
ISNI:       0000 0004 6494 4713
Awarding Body: University of Greenwich
Current Institution: University of Greenwich
Date of Award: 2015
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The main objective of this study was to investigate different manufacturing processes claimed to promote inclusion complexation between different drugs and cyclodextrins (econazole and α-cyclodextrin; indomethacin and methyl-β-cyclodextrin; olanzapine and methyl-β-cyclodextrin; flurbiprofen and methyl-β-cyclodextrin) in order to enhance the apparent solubility and dissolution properties of drugs. Specifically, the effectiveness of supercritical carbon dioxide processing for the preparation of solid drug-cyclodextrin inclusion complexes was investigated and compared to other preparation methods. Nitrate, besylate, sulfosalicylate dihydrate and maleate salts of econazole were synthesised. The solid drug-cyclodextrin inclusion complexes were prepared by physical mixing, freeze drying from aqueous solution and processing with supercritical carbon dioxide. The complexes were evaluated by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, 1H-nuclear magnetic resonance (nuclear Overhauser effect correlation spectroscopy and inversion recovery T1 measurement experiments), and dissolution rate studies. Inclusion yield (%) studies of econazole base into α- and methyl-β-cyclodextrin were conducted in supercritical carbon dioxide to investigate the influence of pressure, temperature and contact time on the inclusion. All the working parameters (pressure, temperature and contact time) played a significant role in the inclusion of econazole base into cyclodextrins. Isothermal titration calorimetric studies of econazole besylate and sulfosalicylate dihydrate salts and α-cyclodextrin confirmed the formation of complexes between the salts and α-cyclodextrin in a 1:1 stoichiometry. Different degrees of crystallinity were observed in the analyses of products prepared by various methods, suggesting the possibility of drug-cyclodextrin interactions of different efficiencies, which may give rise to different degrees of inclusion formation and/or crystallinity of the sample. Nevertheless, products obtained by the freeze-drying and supercritical carbon dioxide-inclusion methods were among the ones showing the highest interaction between the drug and the cyclodextrin. All systems based on α-cyclodextrin and methyl-β-cyclodextrin exhibited greater drug release profiles than the drug alone. Solid state complexation using supercritical carbon dioxide processing proved to be useful complexation method for econazole and its salts into α-cyclodextrin; indomethacin, olanzapine and flurbiprofen into methyl-β-cyclodextrin. The freeze drying method produced highly amorphous and rapid dissolving complexes; however, it was characterised by long, energy-intensive processing steps. Supercritical carbon dioxide inclusion method was shown to be an efficient approach for the preparation of solid-state inclusion complexes. It is an efficient and economic process that allows the formation of solid complexes based in strong intermolecular forces in high yield in a single step avoiding the use of organic solvents and the problems associated with their residues.
Supervisor: Alexander, Bruce D. ; Wicks, Stephen R. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry