Design and Characterization of Stable β-Caryophyllene-loaded Nanoemulsions: A Rational HLB-Based Approach for Enhanced Volatility Control and Sustained Release

chemistry Medicinal and pharmaceutical chemistry Nano- and molecular-scale electronics Nano-biomaterials and bioscience Nanomagnetics Nanomaterials, thin films and nanointerfaces Nanomedicine Nanometrology and nanomechanics Nano-optics Nanopatterning, self-assembly and nanofabrication Nanostructures for energy and sensing applications Natural products chemistry Organo main group chemistry Other nanotechnology (unclassified) Other organic chemistry (unclassified) Photochemistry and photovoltaics Physical organic chemistry Supramolecular chemistry Phytochemicals with therapeutic potential have garnered increasing interest in recent years for their natural origin, multi-target pharmacological effects, and generally favorable safety profiles. One such compound, β-caryophyllene (BCP), a bicyclic sesquiterpene found in essential oils of various plants such as Cannabis sativa, Clove (Syzygium aromaticum), and Black pepper (Piper nigrum), has demonstrated promising analgesic, anti-inflammatory, antioxidant, and anticancer properties [1–3]. Its activity as a selective CB2 receptor agonist has made BCP an especially attractive candidate for developing novel anti-inflammatory and neuroprotective therapies. BCP faces significant challenges in pharmaceutical formulation due to its volatility, low stability under acid environments, and low aqueous solubility. To address these limitations, we developed and characterized BCP-loaded nanoemulsions as a nanocarrier system to improve stability and bioavailability. A systematic, quantitative approach was employed to determine the optimal hydrophilic-lipophilic balance (HLB) for surfactants used in formulation, yielding an optimal range between 12.0 and 14.5. Ternary phase diagrams revealed that nanoemulsions could be obtained under high water content (>70%), low oil content (<10%), and minimal surfactant concentration. Nevertheless, colloidal stability experiments indicated that a co-surfactant was needed to avoid coalescence. In this context, nanoemulsions incorporating 6–8% BCP showed high encapsulation efficiency (>90%) and exhibited kinetic stability for up to 90 days, as confirmed by thermogravimetric analysis (TGA) and visual inspection. Notably, BCP evaporation was significantly reduced in optimized formulations. These findings highlight the critical role of tailored surfactant selection in nanoemulsion stability and offer valuable insights into the design of stable, scalable nanoformulations for hydrophobic phytochemicals.

phytocannabinoid; nanoemulsions, pharmaceutical development, nanotechnology, sesquiterpenes. When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information: Baranda, E. R.; Santos, J. S.; Toledo, A. L. M.; Barradas, T. N. Beilstein Arch. 2025, 202536. doi:10.3762/bxiv.2025.36.v1 Citation data can be downloaded as file using the "Download" button or used for copy/paste from the text window below. Citation data in RIS format can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Zotero. © 2025 Baranda et al.; licensee Beilstein-Institut. This is an open access work licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-archives.org/xiv/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this work could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.