This study investigated the presence of specific drug–excipient interactions in amorphous solid dispersions of lapatinib (LB) and four commonly used pharmaceutical polymers, including Soluplus, polyvinylpyrrolidone vinyl acetate (PVPVA), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and hydroxypropylmethylcellulose phthalate (HPMCP). Based on predicted pK a differences, LB was hypothesized to exhibit a specific ionic interaction with HPMCP, and possibly with HPMCAS, while Soluplus and PVPVA were studied as controls without ionizable functionality. Thermal studies showed a single glass transition (T g) for each dispersion, in close agreement with predicted values for Soluplus, PVPVA, and HPMCAS systems. However, the T g values of LB–HPMCP solid dispersions were markedly higher than predicted values, indicating a strong intermolecular interaction between LB and HPMCP. 15N solid-state NMR provided direct spectroscopic evidence for protonation of LB (i.e., salt formation) within the HPMCP solid dispersions. 1H T 1 and 1H T 1ρ relaxation studies of the dispersions supported the ionic interaction hypothesis, and indicated multiple phases in the cases of excess drug or polymer. In addition, the dissolution and stability behavior of each system was examined. Both acidic polymers, HPMCAS and HPMCP, effectively inhibited the crystallization of LB on accelerated stability, likely owing to beneficial strong intermolecular hydrogen and/or specific ionic bonds with the acidic polymers. Soluplus and PVPVA showed poor physical properties on stability and subsequently poor crystallization inhibition.