From solubilizers to release stabilizers: mechanistic design rules for cyclodextrin-based oral drug delivery

Abstract

Cyclodextrins (CDs) are widely deployed to improve the performance of poorly water soluble drugs, yet their role is still often framed narrowly as empirical “solubilizers.” This review reframes CDs as predictable stabilizers by connecting host–guest thermodynamics, stability constants (K_1:1), complexation efficiency (CE), and ΔG_bind, to quantitative kinetic outcomes that control exposure: supersaturation trajectories, induction time (t_ind), and intrinsic dissolution rate (IDR). We synthesize evidence across native and derivative CDs (HP-β-CD, SBE-β-CD, RM-β-CD, γ-CD) and across hybrid architectures (nanosponges, polymer- and lipid based systems). A practitioner-oriented framework maps drug motifs and speciation at intestinal pH to derivative choice, then prescribes when to add polymers/surfactants to secure recrystallization resistance. Templates for measurement (phase solubility, t_ind, IDR, XRPD/DSC) and a computational toolbox (docking → MD → ΔG estimation; QSPR/ML) translate ΔG/K/CE into effect sizes in log(S/S₀) and t_ind. We codify reporting standards (raw points, CE with CI, buffer/pH/ionic strength, DS/vendor) and common pitfalls (misreading AN/BS curvature, filter adsorption, confusing complex precipitation with drug recrystallization). The review culminates in decision trees and design rules that elevate CDs from trial and error excipients to mechanistically rational stabilizers, supporting robust and reproducible formulation design in oral delivery.

Graphical abstract