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

## TL;DR

This paper presents a scalable method to synthesize capsaicinoids and improve their water solubility using cyclodextrins, enabling broader use in food, pharmaceuticals, and agriculture.

## Contribution

The first pilot-scale continuous flow synthesis of capsaicinoids and a formulation strategy using cyclodextrins to enhance solubility.

## Key findings

- A continuous flow synthesis of capsaicinoids was successfully implemented at pilot scale.
- Cyclodextrin derivatives effectively complexed with capsaicinoids, improving their aqueous solubility.
- NMR spectroscopy confirmed a 1:1 host–guest stoichiometry and key intermolecular interactions.

## Abstract

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.