Self-Assembly of Cyclodextrins and Their Complexes in Aqueous Solutions

Abstract

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.

Aggregation of Cyclodextrins: Fundamental Issues and Applications

“…In CD solutions, dynamic light scattering (DLS) [31,32] and transmission electron microscopy (TEM) [32] have provided reliable evidence of the aggregation phenomenon. The latter has been recognized by several research groups that identified aggregates of different shapes, including spherical and elongated particles, welded fibers, and rods [1,2,19,29].…”

“…[2,3,30]). However, the mechanisms of CD aggregation and CD complex aggregation have not yet been fully understood.…”

“…However, the full characterization of the CD aggregation behavior by these techniques has been hampered by the poor stability of the aggregates, which makes them sensitive to disruptive side effects [2,32].…”

“…The aggregation of single CDs and CD-guest complexes, in water, has been described in a number of recent studies [2,3,13,31,37,40,41]. Despite the efforts for understanding the factors that govern inclusion/binding with guest molecules, the precise manner in which CD molecules aggregate and the cooperative effects underlying this phenomenon are much less studied and still far from consensual.…”

“…This involves both the hydrophobic and hydrophilic moieties of such molecules and induces the formation and growth of the so-called self-assembled structures. This is a spontaneous process in which the system components form ordered aggregates, typically involving an enthalpy gain in solvation, due to hydrogen bond formation, and possibly a gain in the entropy of bulk water (hydrophobic effect) [1][2][3]. The process is promoted by balanced attractive and repulsive interactions between molecules, or specific moieties, occurring from a less organized state (e.g., a solution or a disordered aggregate) to a final ordered state (e.g., a crystal).…”