According to the pH-partition hypothesis, the aqueous solution adjacent to a membrane is a mixture of the ionization states of the permeating molecule at fixed Henderson-Hasselbalch concentrations, such that each state passes through the membrane in parallel with its own specific permeability. An alternative view, based on the assumption that the rate of switching ionization states is instantaneous, represents the permeation of ionizable molecules via an effective Boltzmann-weighted average potential (BWAP). Such an assumption is used in constant-pH molecular dynamics simulations. The inhomogeneous solubility-diffusion framework can be used to compute the pH-dependent membrane permeability for each of these two limiting treatments. With biased WTM-eABF molecular dynamics simulations, we computed the potential of mean force and diffusivity of each ionization state of two weakly basic small molecules: nicotine, an addictive drug, and varenicline, a therapeutic for treating nicotine addiction. At pH = 7, the BWAP effective permeability is greater than that determined by pH-partitioning by a factor of 2.5 for nicotine and 5 for varenicline. To assess the importance of ionization kinetics, we present a Smoluchowski master equation that includes explicitly the protonation and deprotonation processes coupled with the diffusive motion across the membrane. At pH = 7, the increase in permeability due to the explicit ionization kinetics is negligible for both nicotine and varenicline. This finding is reaffirmed by combined Brownian dynamics and Markov state model simulations for estimating the permeability of nicotine while allowing changes in its ionization state. We conclude that for these molecules the pH-partition hypothesis correctly captures the physics of the permeation process. The small free energy barriers for the permeation of nicotine and varenicline in their deprotonated neutral forms play a crucial role in establishing the validity of the pH-partitioning mechanism. Essentially, BWAP fails because ionization kinetics are too slow on the time scale of membrane crossing to affect the permeation of small ionizable molecules such as nicotine and varenicline. For the singly protonated state of nicotine, the computational results agree well with experimental measurements ( = 1.29 × 10 cm/s), but the agreement for neutral ( = 6.12 cm/s) and doubly protonated nicotine ( = 3.70 × 10 cm/s) is slightly worse, likely due to factors associated with the aqueous boundary layer (neutral form) or leaks through paracellular pathways (doubly protonated form).