From Mechanochemically Driven Complexation and Multimodal Characterization to Stability and Toxicological Insight: A Study of Cinnarizine–β-Cyclodextrins Complexes

<b>Background:</b> Cinnarizine (CIN) is a poorly soluble drug used in the treatment of vestibular disorders. Its solubility can be improved by complexation with cyclodextrins (CDs). This study focused on the preparation of 1:1 CIN/CD complexes with β-cyclodextrin (βCD) and its derivatives hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD) by mechanical activation. <b>Methods:</b> Complexes were obtained under optimized grinding conditions using a high-energy vibrational mill with ZrO₂ grinding media. Solid products were characterized by DSC, TGA, XRPD, and FTIR spectroscopy. Dissolution studies were performed in phosphate buffer (pH 4.5). The effect of βCD and HPβCD on CIN stability was assessed under hydrolytic (acidic, neutral, and basic) and oxidative conditions. A stability-indicating UHPLC-DAD-HRMS method was developed and validated, enabling CIN quantification in the presence of degradation products, whose structures were proposed based on HRMS/MS data. Potential toxicity, bioaccumulation, and mutagenicity of degradation products were predicted using QSAR modeling. Accelerated stability studies (40 °C, 75% RH) were conducted to evaluate long-term stability. <b>Results:</b> Solid-state analyses confirmed CIN/CD interactions in the ground products. The highest dissolution efficiency was observed for CIN/HPβCD complexes, while CD complexation did not alter CIN permeability in biomimetic membrane assays. CIN and its complexes demonstrated satisfactory chemical stability, with no degradation products detected under accelerated conditions. <b>Conclusions:</b> Solid-state complexes of CIN with CDs enhanced dissolution without compromising stability, supporting their potential as promising candidates for novel pharmaceutical formulations.