Intensified Tricaprin Synthesis Using Multifrequency Ultrasound and Its Application as a Topical Drug Delivery System for Fungal Infections

The study presents the ultrasound-assisted synthesis of tricaprin using a triple frequency hexagonal ultrasonic reactor. The esterification of capric acid and glycerol was catalyzed by para-toluene sulfonic acid (p-TSA) at a 500 g scale. A one-factor-at-a-time approach was used to optimize reaction parameters under both conventional and ultrasonic conditions. Under optimized ultrasonic conditions of a 4:1 molar ratio, 150 W ultrasound power, 70% duty cycle, 1.5% p-TSA loading, and combined frequencies of 22–33–48 kHz, the tricaprin yield reached the maximum of 95.7% as determined by gas chromatography–flame ionization detector (GC–FID) analysis. The pseudo-first-order rate constant significantly increased to 0.0167 min^–1 in the ultrasound-assisted approach compared to 0.0035 min^–1 in the conventional method, while energy consumption was reduced by 19.2%, requiring only 1554.8 kJ against 1924.5 kJ. Among the catalysts evaluated, p-TSA and Amberlyst-15 showed the best catalytic performance among the homogeneous and heterogeneous categories, respectively. The synthesized tricaprin was formulated into a topical antifungal Bigel. Ex-vivo skin permeation studies demonstrated superior performance compared to a marketed formulation (Lulimac gel), with only 3.57% of the drug remaining unpenetrated in the Bigel, compared to 50% in the marketed product. Additionally, the bigel achieved significantly higher skin retention of 18%, while the marketed formulation showed only 0.45%. Overall, the study demonstrates the advantage of ultrasound technology for efficient tricaprin synthesis and its successful application in enhanced topical drug delivery.