From Hemp to CBD Crystals: A Scaled-Up Procedure for the Selective Extraction, Isolation, and Purification of Cannabidiol.

The isolation of cannabidiol (CBD) with a purity greater than 99%, while avoiding the presence of Δ9-tetrahydrocannabinol (THC), is essential for both exploring CBD applications and its commercialization. The scientific literature lacks robust and scalable protocols for obtaining pure CBD, instead primarily focusing on obtaining hemp extracts with higher cannabinoid content. Herein, we present a complete procedure for obtaining pure CBD crystals, starting from an industrial hemp cultivar. The protocol includes thermal decarboxylation of cannabinoids, supercritical CO extraction, winterization of the extract, CBD purification via sequential C18 reverse-phase silica filtration, silica gel chromatography, and selective crystallization. Each step has been carefully optimized to identify the best solvent, solvent/extract ratio, and silica/extract ratio to minimize CBD loss in waste fractions and to enable solvent and material recovery for recycling, aligning with a sustainable perspective. The scale-up of the procedure to 100-600 g for each step demonstrated the feasibility of our protocol for the obtainment of pure CBD crystals. An overall 52% yield of CBD with a purity exceeding 99% and a negligible THC content was achieved.