The first semi-continuous Pressurized Liquid Extraction (PLE) of hemp threshing residue with ethanol was carried out according to a 32 full factorial experimental design with pressure and temperature as independent variables at 8-10-12 MPa and 323-333-343 K, respectively. The total- and cannabidiol (CBD) yield curves were fitted to the modified two-parameter Brunner equation. Best results, concerning CBD, can be achieved at 12 MPa and 343 K. Solvent mass-consumption and operation time were considerably decreased compared to a previous supercritical fluid extraction study on the same material. Furthermore, the concentration profiles were evaluated to study the mass transfer. The winterized dry extracts were further studied in a methanol-hexane-water ternary system concerning CBD distribution ratio, showing high methanol dependency.

Mitragynine is an “atypic opioid” analgesic with an alternative mechanism of action and a favorable side-effect profile. Our aim was to optimize the alkaloid extraction procedure from kratom leaves and to determine and isolate the most relevant compounds capable of penetrating the central nervous system. The PAMPA-BBB study revealed that mitragynine and its coalkaloids, speciociliatine, speciogynine, and paynantheine, possess excellent in vitro BBB permeability. An optimized sequence of CPC, flash chromatography, and preparative HPLC methods was used to isolate the four identified BBB+ alkaloids. To improve the bioavailability of the isolated alkaloids, their cyclodextrin (CD) complexation behavior was investigated via affinity capillary electrophoresis using almost 40 CD derivatives. The apparent alkaloid–CD complex stability constants were determined and compared, and the most relevant CDs phase-solubility studies were also performed. Both the neutral and negatively charged derivatives were able to form complexes with all four kratom alkaloids. It was found that cavity size, substituent type, and degree of substitution also influenced complex formation. The negatively charged Sugammadex, Subetadex, and the sufoalkylated-beta-CD analogs were able to form the most stable complexes, exceeding 1000 M⁻¹. These results serve as a good basis for further solubility and stability enhancement studies of kratom alkaloids.