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

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.