Considerations In Using Cyclodextrins As Solubilizers For Early Toxicology Studies

By Lisa Z. Crandall, MS, Velesco Pharma

Early stage drug development can frequently be hindered by compound solubility and the need to deliver large doses to animals with as little vehicle toxicity as possible. Formulators have a powerful tool in the Cyclodextrin (CD) molecules; however there are several complicating factors that must be considered.

Cyclodextrins are cyclic oligosaccharide molecules (of at least 6 subunits) derived from starch, which form structures with lipophilic inner cavities and hydrophilic outer surfaces. In essence, they create a lipophilic “bucket” (Figure 1.) that can interact with a lipophilic compound, creating an inclusion complex. This interaction and the exposure of the hydrophilic outer Cyclodextrin surface allow CD molecules to solubilize some poorly soluble lipophilic compounds. Modified Cyclodextrins are highly water-soluble themselves.

There are several Cyclodextrin versions available, but the most commonly used are substituted α, β, or γ- CDs that contain 6, 7, or 8 glucose molecules respectively. The higher the number of glucose molecules, the larger the diameter of the inner “bucket” (Figure 2) (approximately 0.5, 0.6, and 0.8 nm respectively for α, β, and γ CD). Substitutions are typically hydroxypropyl, although many other options are available. Formulation with Cyclodextrins has also been shown to improve chemical and physical stability of some compounds, possibly due to their behaving as a “molecular shield”. For early toxicology studies, this is an added bonus to using CDs, but usually not a pivotal reason for their use.