Berberine Processing by Gas Antisolvent: A Strategy to Modulate Its Solid-State Properties

Berberine is widely used in pharmaceutical formulations; however, its high moisture sensitivity and the presence of interconvertible hydration states compromise product reproducibility and quality, requiring effective solid-state control strategies. In this context, supercritical CO₂ micronization techniques, such as the Gas Antisolvent (GAS) method, represent sustainable alternatives for inducing physical modifications without altering chemical structure. In this study, a methanolic solution of berberine (1 mg·mL^-1) was processed by GAS at 80 bar and 35 °C, followed by CO₂ washing (10 mL·min^-1). The resulting particles were characterized by SEM, XRD, and FTIR. GAS processing significantly reduced the mean particle size (from 15.62 ± 10.03 µm to 12.79 ± 9.97 µm; p < 0.05) and produced a more irregular and fragmented morphology. XRD patterns indicated preservation of the crystalline phase with reduced crystallinity and signs of an amorphous fraction, while FTIR spectra confirmed maintenance of functional groups. Overall, GAS processing promoted particle size reduction and controlled structural modifications without compromising the molecular integrity of berberine, highlighting its potential for improving technological performance in oral formulations.