Structure elucidation of the tetrahydrocannabinol complex with randomly methylated β-cyclodextrin

The low aqueous solubility of the bioactive cannabinoid tetrahydrocannabinol (THC) is a serious obstacle for the development of more efficient administration forms. In this study the aqueous solubility of THC was tested in the presence of alpha-, beta- and gamma-CD, and randomly methylated beta-CD (RAMEB). It was found that only RAMEB was able to increase the aqueous solubility of THC to a significant level. A THC concentration of about 14 mg/ml was reached by using a 24% (187 mM) RAMEB solution, which means an increase in solubility of four orders of magnitude. The resulting THC/RAMEB complex was investigated through phase-solubility analysis, complemented by H-1 NMR, NOESY- and UV-studies in order to obtain details on the stoichiometry, geometry and thermodynamics of the complexation. The binding ratio of THC to CD was found to be 2:1, with the second THC molecule bound by non-inclusion interactions. Based on the obtained results a model for the complex structure is presented. Stability of the complex under laboratory room conditions was tested up to 8 weeks. Results show that complexation with RAMEB seems to be promising for the development of water-based THC formulations. (c) 2006 Elsevier B.V. All rights reserved.