Self-association of cyclodextrins and cyclodextrin complexes in aqueous solutions.

Cyclodextrins (CDs) are oligosaccharides that self-assemble in aqueous solutions to form transient clusters, nanoparticles and small microparticles. The critical aggregation concentration (cac) of the natural αCD, ßCD and γCD in pure aqueous solutions was estimated to be 25, 8 and 9 mg/ml, respectively. The cac of 2-hydroxypropyl-ß-cyclodextrin (HPßCD), that consists of mixture of isomers, was estimated to be significantly higher or 118 mg/ml. Addition of chaotropic agents (i.e. that disrupts non-covalent bonds such as hydrogen bonds) to the aqueous media increases the cac. Formation of drug/CD complexes can increase or decrease the cac. Due to the transient nature of the CD clusters and nanoparticles they can be difficult to detect and their presence is frequently ignored. However, they have profound effect on the physiochemical properties of CDs and their pharmaceutical applications. For example, the values of stability constants of drug/CD complexes can be both concentration dependent and method dependent. Like in the case of micelles water-soluble polymers can enhance the solubilizing effect of CDs. Also, formation of drug/CD complex nanoparticles appears to increase the ability of CDs to enhance drug delivery through some mucosal membranes.

2-Hydroxypropyl-ß-Cyclodextrin Aggregates: Identification and Development of Analytical Techniques.

It is extremely important for pharmaceutical formulators to have analytical methodology that provides efficient detection and quantification of HPßCD aggregates. Five different methods were then evaluated for their potential to detect these aggregates and to determine critical aggregation concentration (cac): osmometry, viscometry, tensiometry, dynamic light scattering (DLS), and permeability studies. Overall, tensiometry was an inadequate method with which to study HPßCD aggregation, since the addition of HPßCD to water resulted in only minor changes in surface tension. Osmolality and viscosity studies have shown that for HPßCD, solute⁻solvent interactions are the main contributors for the observed deviation from ideality. These deviations might be related to the presence of aggregates. The DLS method proved to be an effective method with which to detect HPßCD aggregates and estimate their hydrodynamic diameter, although it presented some limitations concerning their quantification. In terms of the assessed methods, permeation studies were shown to be the best to study HPßCD aggregation phenomena, since they were the only method where the detection of aggregates and the determination of apparent cac values was possible. Also, it was the least invasive for the HPßCD samples and the method that provided more conclusive data. Results suggested that HPßCD, as expected, has less tendency to form aggregates than ßCD.

Self-Assembly of α-Cyclodextrin and ß-Cyclodextrin: Identification and Development of Analytical Techniques.

Recently, it has been shown that cyclodextrins (CDs) self-assemble in aqueous solutions to form aggregates. Such aggregation can give rise to formation of particulate matter in aqueous solutions. However, the analytical methodology available to detect and quantify these aggregates is still quite inadequate. Here, 5 different methods for evaluation of CD aggregate formation and determination of the critical aggregation concentration are evaluated: osmometry, viscosity, surface tension, dynamic light scattering, and permeability studies. Both the viscosity and surface tension methods applied were inadequate for aggregate detection, whereas the osmometry method can be used to study CD aggregation but with some limitations. Dynamic light scattering has also some limitations although it can be applied to detect CD aggregates and to estimate their hydrodynamic diameter. Overall, permeation studies proved to be the best method to detect and determine critical aggregation concentration. These results suggested that ß-cyclodextrin (ßCD) has higher tendency to aggregate than α-cyclodextrin (αCD). Filtration of αCD and ßCD solutions affected the aggregate size distribution by breaking larger aggregates in to smaller ones that then reassembled to regenerate the larger ones upon storage. The osmolality studies showed that in aqueous αCD and ßCD solutions, solute-solute interactions are favored over solute-solvent interactions with consequent CD aggregate formation.

Self-Assembly of Cyclodextrins and Their Complexes in Aqueous Solutions.

Cyclodextrins (CDs) are enabling pharmaceutical excipients that can be found in numerous pharmaceutical products worldwide. Because of their favorable toxicologic profiles, CDs are often used in toxicologic and phase I assessments of new drug candidates. However, at relatively high concentrations, CDs can spontaneously self-assemble to form visible microparticles in aqueous mediums and formation of such visible particles may cause product rejections. Formation of subvisible CD aggregates are also known to affect analytical results during product development. How and why these CD aggregates form is largely unknown, and factors contributing to their formation are still not elucidated. The physiochemical properties of CDs are very different from simple amphiphiles and lipophilic molecules that are known to self-assemble and form aggregates in aqueous solutions but very similar to those of linear oligosaccharides. In general, negligible amounts of aggregates are formed in pure CD solutions, but the aggregate formation is greatly enhanced on inclusion complex formation, and the extent of aggregation increases with increasing CD concentration. The diameter of the aggregates formed is frequently less than about 300 nm, but visible aggregates can also be formed under certain conditions.