Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes

Abstract

Cyclodextrins (CDs) are well known functional excipients for solubilization and stabilization of drugs in aqueous formulations as well as enabling adjuncts for increasing the oral bioavailability of solid dosage forms. More recently a number of the valuable properties of these CDs have been ascribed to nanoparticulate aggregation in addition to its ability to form molecular inclusion complexes. The purpose of this study is to identify and characterize the aggregation of CD inclusion complexes with a model drug, hydrocortisone, in saturated solutions which are more relevant to drug formulation than highly dilute systems. Penetration studies of complexes through membranes and phase solubility relationships were assessed for saturated hydrocortisone solutions with the parent CDs, namely αCD, βCD, γCD or with various water-soluble derivatives, i.e., 2-hydroxypropyl-βCD (HPβCD), 2-hydroxypropyl-γCD (HPγCD) or sulfobutyl ether-β-CD (SBEβCD). The data indicate that βCD and γCD form micro-aggregates with hydrocortisone resulting in non-linear phase-solubility relationships. By contract, the other studies of CDs or CD derivatives were found to form nanoaggregates with hydrocortisone resulting in linear solubilization relationships. Permeability profiles were evaluated for the systems formed and are described in three sections specifically a section (section I) where flux is linear (Fickian) as a function of CD concentration, a section (section II) where flux deviates in a negative fashion from linearity but still increases as the CD concentration increases and a section (section III) where flux is independent of the cyclodextrin concentration. Diminished values of flux can be interpreted based on the formation of nanoaggregates of hydrocortisone/CD complexes. Extrapolation of section I data made it possible to obtain theoretical flux values which could be used to estimate the fraction of complexes and drug which participate in aggregation. The CDs which appeared to demonstrate the lowest tendency to form complex aggregates were αCD and SBEβCD, due to their low complexation efficacy and repulsive forces, respectively. Complex aggregates with these CDs are also smaller with maximum size between 50 and 100 kDa. HPβCD and HPγCD complex aggregates manifested a maximum size above 100 kDa and the fraction of drug which participates in complex aggregation with these species is higher than for the other materials assessed. In the case of 90 mM HPγCD solution, data suggest that 87% of all hydrocortisone is tied up in the form of aggregates. These high concentrations were confirmed by TEM which found most particles in the 3-5 nm range but rarely particles as large as 10 and 20 nm. Speculation on the mechanism of the aggregation processes and equilibrium constants are provided but these tend to punctuate our limited understanding of these potentially important processes.