<p>Elucidating the pharmacokinetic profiles of different chemical forms of nicotine (free-base versus protonated)—particularly their differences in biological absorption—is critically important for balancing its potential clinical applications in neurodegenerative disease therapy with effective management of its inherent addiction risk. Current empirical observations regarding which form exhibits superior absorption remain significantly divergent. This study employs an aerosol delivery model to compare the permeability (simulated absorption) of the two nicotine forms in solution by quantifying the amount absorbed and the residual nicotine after aerosol penetration through a simulated solution barrier. The results demonstrate that free-base nicotine exhibits higher solution absorption than its protonated counterpart. The superior absorption of free-base nicotine is primarily attributed to its diffusion from the particulate phase to the gas phase within aerosols, facilitating efficient mass transfer across the gas–liquid interface. These findings provide an in vitro experimental basis for further evaluation of the potential differences in human absorption efficiency between nicotine forms, thereby supporting the development of nicotine-based pharmaceuticals.</p>