Thermal, Spectroscopic, and Dielectric Investigation of Hydrogen-Bonded Lapatinib–PVP Amorphous Solid Dispersions with Enhanced In Vitro Cytotoxicity

Lapatinib (LAP), a dual EGFR/HER2 tyrosine kinase inhibitor used in HER2-positive breast cancer, exhibits poor aqueous solubility that limits its oral bioavailability. Although amorphous solid dispersions (ASDs) can improve LAP solubility, the molecular mechanisms and drug-induced molecular mobility remain insufficiently understood. This study aimed to elucidate the molecular mobility and relaxation dynamics of LAP-based ASDs using broadband dielectric spectroscopy (BDS), with particular emphasis on drug–polymer interactions. LAP–polyvinylpyrrolidone (PVP) ASDs with drug-to-polymer ratios of 10:90 (ASD1), 20:80 (ASD2), 30:70 (ASD3), and 40:60 (ASD4) were prepared by solvent evaporation and characterized using TGA, DSC, BDS, FTIR, XRD, and DFT. Drug solubility, dissolution, and cytotoxicity were additionally evaluated. TGA demonstrated enhanced thermal stability of LAP in the polymer matrix, with T onset increasing from 488 K for crystalline LAP to approximately 655 K for ASD1 and 536 K for ASD2–ASD4. DSC and BDS revealed concentration-dependent plasticization by LAP, with T g decreasing from 406 K for PVP to 398, 384, and 371 K for ASD1, ASD2, and ASD3, respectively. BDS identified a single cooperative α-relaxation in the ASDs, supporting molecular miscibility, while changes in fragility and β- and γ-relaxation activation energies demonstrated concentration-dependent modulation of molecular mobility. XRD confirmed complete amorphization in ASD1, ASD2, and ASD3, whereas residual crystallinity was observed in ASD4. FTIR and DFT supported hydrogen bonding as a key stabilizing interaction. The ASDs markedly improved LAP solubility and dissolution compared with crystalline LAP, with ASD2 showing the highest dissolution, reaching approximately 90% release at pH 7. Importantly, ASD2 enhanced LAP cytotoxicity against MCF-7 cells, reducing the IC₅₀ by more than fourfold.