Drug-cyclodextrin complexes: an approach to enhance the solubility and dissolution properties of poorly soluble drugs

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.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Greenwich

Year dc:date.issued

2015

Author dc:creator

• Rudrangi, Shashi Ravi Suman

Advisors dc:contributor.advisor

• Alexander, Bruce D.
• Wicks, Stephen R.

• QD Chemistry

Language dc:language

en