Enhancing solubility and stability of piperine using -cyclodextrin derivatives: computational and experimental investigations

Piperine (PP), a natural alkaloid found in black pepper, possesses significant bioactivities. However, its use in pharmaceutical applications is hindered by low water solubility and susceptibility to UV light degradation. To overcome these challenges, we investigated the potential of beta-cyclodextrin (beta CD) and its derivatives with dimethyl (DM beta CD), hydroxy-propyl (HP beta CD) and sulfobutyl-ether (SBE beta CD) substitutions to enhance the solubility and stability of PP. This study employed computational and experimental approaches to examine the complexation between PP and beta CDs. The results revealed the formation of two types of inclusion complexes: the P-form and M-form involving the insertion of piperidine moiety and the methylene-di-oxy-phenyl moiety, respectively. These complexes primarily rely on van der Waals interactions. Among the three derivatives, the PP/SBE beta CD complex exhibited the highest stability followed by HP beta CD, as attributed to maximum atom contacts and minimal solvent accessibility. Solubility studies confirmed the formation of inclusion complexes in a 1:1 ratio. Notably, the stability constant of the inclusion complex was approximately two-fold higher with SBE beta CD and HP beta CD compared to beta CD. The DSC thermograms provided confirmation of the formation of the inclusion complex between the host and guest. These findings highlight the potential of beta CD derivatives to effectively encapsulate PP, improving its solubility and presenting new opportunities for its pharmaceutical applications. [Graphical Abstract]