Cyclodextrins (CDs) are native host systems with inherent ability to form inclusion complexes with various molecular entities, mostly hydrophobic substances. Host cyclodextrins are accommodative to water molecules as well and contain water in the native state. For β-cyclodextrin (β-CD), there is no consensus regarding the number of bound water molecules and the location of their coordination. A number of intriguing questions remain: (1) Which localities of the host’s macrocycle are the strongest attractors for the guest water molecules? (2) What are the stabilizing factors for the water clusters in the interior of β-CD and what type of interactions between water molecules and cavity walls or between the water molecules themselves are dominating the energetics of the β-CD hydration? (3) What is the maximum number of water molecules inside the cavity of β-CD? (4) How do the thermodynamic characteristics of β-CD hydration compare with those of its smaller α-cyclodextrin (α-CD) counterpart? In this study, we address these questions by employing a combination of experimental (DSC/TG) and theoretical (DFT) approaches.

In this short review, recent findings from both theory and experiment regarding the process of hydration of α-, β-, and γ-cyclodextrins are summarized and critically assessed. Key important questions are addressed, including: What factors govern the number of water molecules entrapped in the internal cavity of the host macrocycle? What is the driving force behind this process? What are the “hot spots” for water entrapment inside the host cavity? What is the underlying mechanism of water hydration and dehydration of cyclodextrins? What is the role of the confined water cluster in determining the outcome of the host–guest complexation between cyclodextrins and molecules of inorganic/organic nature? To what extent does water hydration affect the crystalline structure of the cavitand?