Doctoral defense - André Rodrigues Sá Couto

Cyclodextrin aggregates can be either advantageous (production of drug delivery systems) or detrimental (presence of visible particles can be unacceptable) in pharmaceutical intravenous formulations. In order to detect/quantify their formation in pure CD aqueous solutions (αCD, βCD and HPβCD) five analytical methods were assessed: osmometry, viscometry, tensiometry, dynamic light scattering and permeability studies (PeS). PeS proved to be the best method to detect and calculate aggregates’ cac values present in aqueous CD solutions. βCD has higher tendency to self-assemble than αCD and this one higher than HPβCD.

The influence of model drugs on CDs and their complexes physicochemical properties and tendency to self-aggregate was evaluated (i.e. by phase-solubility, osmometry and PeS). In general, increasing CD cavity diameter (αCD << βCD < γCD) led to an increase of model drugs’ apparent solubility. PeS was also for model drugs/CD systems the most effective method to detect and quantify the formation of drug/CD complex‘ aggregates. Methylparaben and Carbamazepine did not promote any change on the apparent cac value of HPβCD, while the remaining studied parabens (ethyl, propyl and butyl) did affect the HPβCD and γCD aggregation behavior increasing their tendency to self-aggregate.

The characterization of solid phases provided good support to liquid phase assays showing identical conclusions.

Urea (water structure modifier) disrupted the CD aggregation by hindering the formation of H-bonds (visually confirmed by decrease of CD solutions’ haziness). Accordingly, permeation studies of aqueous αCD and γCD in presence or absence of urea also suggested the involvement of urea on disturbing aggregation process.