Methotrexate–Cyclodextrin Systems: Molecular Recognition, Formulation Design, and Translational Perspectives

Methotrexate (MTX) remains central to the treatment of rheumatoid arthritis and several malignancies, yet its use is complicated by dose-dependent toxicity, variable oral exposure, photolability, and pH-dependent solubility. Cyclodextrins (CDs) can alter the molecular environment of MTX, but the literature often conflates true inclusion complexes with formulations in which CD merely forms part of a larger carrier. This review critically distinguishes direct MTX–CD complexes, dosage forms built from a preformed complex, CD-containing carriers without direct evidence of cavity occupancy, and covalent MTX–CD conjugates. Particular attention is given to binding stoichiometry, apparent association constants, guest orientation, preparation methods, and the evidence needed to establish inclusion. Both solution-state host–guest association and isolated solid products are considered; however, solid-state changes are treated as supportive evidence rather than as stand-alone proof of cyclodextrin cavity occupancy. Among the limited head-to-head comparisons of native cyclodextrins, β-CD generally showed more favorable MTX recognition than α- or γ-CD, although the magnitude of this difference is method- and condition-dependent. Complexation can improve dissolution, photostability, and oral or local delivery; however, greater solubilization does not necessarily enhance membrane transport. In carrageenan hydrogels, β-CD increased MTX loading and release while reducing membrane permeation, illustrating the importance of the equilibrium between complexed and freely permeating drug. The most promising systems remain preclinical. Progress toward translation will require clearer nomenclature, orthogonal structural characterization, mechanism-resolving controls, and standardized pharmacokinetic and safety studies.