Cyclodextrins: Synthesis, Pharmaceutical Applications, Drug Delivery Systems and Safety Perspectives

Cyclodextrins (CDs) are cyclic oligosaccharides composed of α-(1,4)-linked glucopyranose units that have emerged as multifunctional and versatile pharmaceutical excipients. One of the major challenges in modern drug development is that nearly half of newly discovered drug molecules exhibit poor aqueous solubility, which adversely affects formulation development, bioavailability, and therapeutic efficacy. CDs address this limitation by forming non-covalent inclusion and non-inclusion complexes, thereby enhancing drug solubility, stability, dissolution rate, and overall biopharmaceutical performance. This review provides a comprehensive overview of CDs, including their historical background, structural characteristics, and production through starch conversion by the enzyme cyclodextrin glucanotransferase (CGTase). Special emphasis is placed on the transglycosylation reactions catalyzed by CGTase, including cyclization, coupling, and disproportionation, which play a critical role in CD synthesis. Recent advances in structural elucidation techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, molecular dynamics simulations, and ion mobility mass spectrometry, are also discussed. The pharmaceutical applications of CDs are critically evaluated, with particular emphasis on their roles as solubility enhancers, taste-masking agents, and stabilizers in nanocarrier-based and targeted drug delivery systems. Their applications in cosmetics and dermopharmaceuticals are also explored, particularly in improving formulation stability and enabling controlled drug delivery. Furthermore, the pharmacokinetics, toxicological safety, and regulatory acceptability of various CDs are discussed. Overall, this review highlights the growing importance of CDs as pharmaceutical excipients that bridge supramolecular chemistry and advanced drug delivery systems.