Mechanochemical Activation of Olanzapine in Mixed Solid Dispersions: Impact of Excipients on Release and Permeation...

Background: The key parameters determining the bioavailability of an active pharmaceutical ingredient are its solubility/dissolution rate in physiological fluids and permeability across biological membranes. Highly accurate in vitro prediction of bioavailability is a key issue that typically arises during the development of new drug formulations and the improvement of existing ones. Objectives: The objective of the present work is to study the dissolution/release and permeation of olanzapine (OLZ) from two- and three-component solid dispersions (SDs) with sulfobutylether-β-cyclodextrin (SBE-β-CD) and several pharmaceutical adjuvants as solubilizing agents. Methods: Solid dispersions were prepared by mechanical grinding and characterized with X-ray Phase analysis (PXRD), Fourier Transform Infrared (FTIR) and Raman spectroscopy, Differential Scanning Calorimetry (DSC), and Scanning Electron Microscopy (SEM). Results: Raman spectroscopy was shown to be the best for revealing the interactions of OLZ with SBE-β-CD and γ-aminobutyric acid (GABA) in the three-component SD. The kinetic dependences of OLZ release and diffusion through the cellulose membrane were thoroughly described by quantitative parameters and classified according to the drug release mechanism. Significant improvement of release rate, OLZ concentration, and permeation with SDs compared to the pure OLZ was demonstrated. Conclusions: It was shown that the selected dispersions were stable when stored under normal conditions but underwent changes upon exposure to elevated temperature and humidity. The nature of these changes was determined by the properties of the components and their mutual interactions.