Pilot-Scale Continuous Flow Synthesis of Capsaicinoids and Their Formulation with Cyclodextrins

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 <i>N</i>-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.