Enhancing solubility and stability of sorafenib through cyclodextrin-based inclusion complexation: in silico and in vitro studies

Sorafenib (SOR) is an oral multikinase inhibitor that effectively hampers the growth and spread of cancer cells by targeting angiogenesis and proliferation. However, SOR tablets (Nexavar) have limited oral bioavailability, ranging from 38% to 49%, due to their low water solubility. To address this issue, cyclodextrins (CDs), widely used to enhance the solubility and stability of lipophilic drugs by encapsulating them within their molecular structure, were considered in this study. We focused on bcyclodextrin (bCD) and its derivatives, including hydroxypropyl-b-cyclodextrin (HPbCD), dimethyl-bcyclodextrin (DMbCD), sulfobutylether-b-cyclodextrin (SBEbCD), and compared them with gcyclodextrin (gCD) for generating inclusion complexes with SOR. The 200 ns molecular dynamics simulations revealed that SOR could form inclusion complexes with all CDs in two possible orientations: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form), primarily driven by van der Waals interactions. Among the four bCD derivatives studied, SOR exhibited the highest number of atom contacts with SBEbCD and demonstrated the lowest solvent accessibility within the hydrophobic cavity of SBEbCD. These findings correlated with the highest binding affinity of SOR/SBEbCD complex determined by SIE, MM/GBSA, and MM/PBSA methods. Experimental results further supported our computational predictions, in which SBEbCD exhibited a stability constant of 940 M-1 at 25 degrees C, surpassing bCD's stability constant of 210 M-1. Taken together, our results suggest that the modified CDs, particularly SBEbCD, hold promising potential as an efficient molecular encapsulating agent for SOR, offering improved solubility and stability for this lipophilic drug.