Capsaicinoids are the principal compounds responsible for the pungency of chili peppers
and are widely used as food additives as well as in pharmaceutical and cosmetic formulations
or potential agrochemicals. However, capsaicin and its derivatives have poor aqueous
solubility, which limits their broader application. In this study, we report the first
pilot-scale continuous flow synthesis of capsaicin, dihydrocapsaicin, and nonivamide,
using sequential oxime formation, hydrogenation, and N-acylation steps. To increase
the water solubility of these capsaicinoids, we systematically investigated their
inclusion complex formation with various α- and β-cyclodextrin (CD) derivatives. Phase-solubility
analyses and stability constant determinations were conducted to evaluate the complexation
efficiency. Furthermore, 1D and 2D NMR spectroscopy confirmed 1:1 host–guest stoichiometry
and revealed key intermolecular interactions between the CDs and the aliphatic moieties
of the capsaicinoids. Overall, these results provide a scalable synthetic pathway
and an efficient formulation strategy for capsaicinoid-based applications, which are
particularly valuable in the pharmaceutical industry, food production, or agricultural
processing, where aqueous solubilization and safety compliance are critical due to
the potential irritant effects of capsaicinoid-containing powders or sprays.
