Preparation, characterization and evaluation of cefixime ternary inclusion complexes formated by mechanochemical strategy

Abstract

In an endeavor to ameliorate the solubility and subsequent oral bioavailability of Cefixime (CEF), a drug noted for its deficient water solubility, the formulation of ternary inclusion complexes was executed utilizing hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), in conjunction with N-methyl-D-glucaminet (MG). This development was realized through the application of a mechanochemistry technique, acknowledged for its “green” credentials. The complexes' physicochemical attributes were meticulously examined through various analytical techniques: Fourier-transform infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Powder X-ray Diffractometry (XRD), and Scanning Electron Microscopy (SEM). Notably, the ternary complexes exhibited an uplift in apparent drug solubility, especially when juxtaposed with binary complexes. A prominent augmentation was perceived in the stability constant (Kc) and complexation efficiency (CE) when MG was integrated into the ternary complexes with HP-β-CD or SBE-β-CD. Further exploratory molecular docking and molecular dynamics studies underscored MG’s role in augmenting complex stability by serving as a bridge between CEF and cyclodextrins (CDs). The parallel artificial membrane permeability assay (PAMPA) indicated a conspicuous enhancement of CEF permeability in the ternary complexes relative to the control–free CEF. The particle size and zeta potential of the mechanochemically processed ternary complexes in liquid form were assessed using Dynamic Light Scattering (DLS). Moreover, in vivo evaluations revealed the ternary complexes to manifest notably superior oral bioavailability when compared to unadulterated CEF. Lastly, through the rapid storage assay, a heightened physicochemical stability was observed in the mechanochemically synthesized CEF ternary supramolecular inclusion complexes, compared to the pure drug, intimating a pioneering approach for the oral delivery of CEF, ensuring improved bioavailability.

Graphical abstract