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

Abstract

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 β-cyclodextrin (βCD) and its derivatives with dimethyl (DMβCD), hydroxy-propyl (HPβCD) and sulfobutyl-ether (SBEβCD) substitutions to enhance the solubility and stability of PP. This study employed computational and experimental approaches to examine the complexation between PP and βCDs. 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/SBEβCD complex exhibited the highest stability followed by HPβCD, 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 SBEβCD and HPβCD compared to βCD. The DSC thermograms provided confirmation of the formation of the inclusion complex between the host and guest. These findings highlight the potential of βCD derivatives to effectively encapsulate PP, improving its solubility and presenting new opportunities for its pharmaceutical applications.

Communicated by Ramaswamy H. Sarma

Keywords:

• Piperine
• β-cyclodextrin derivatives
• inclusion complexes
• solubility enhancement
• in silico and in vitro studies

Acknowledgments

S.A. and A.A. thank the Scholarship Program for ASEAN and NON-ASEAN Countries, Graduate School, Chulalongkorn University (CU) and 90^th anniversary of CU Fund (Ratchadaphiseksomphot Endowment Fund). PM would like to acknowledge the financial support from Fundamental Fund of Khon Kaen University. Computational resources are provided by the Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, CU and the Vienna Scientific Cluster (VSC). We thank the ASEAN-European Academic University Network (ASEA-UNINET) for a short visit grant.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The 90th Anniversary of Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund); Faculty of Medicine Khon Kaen University