In the pharmaceutical industry, salt is commonly used to improve the oral bioavailability of poorly soluble compounds. Currently, there is a limited understanding on the solubility requirement for salts that will translate to improvement in oral exposure. Despite the obvious need, there is very little research reported in this area mainly due to the complexity of such a system. To our knowledge, no report has been published to guide this important process and salt solubility requirement still remains unanswered. Physiologically based pharmacokinetic (PBPK) modeling offers a means to dynamically integrate the complex interplay of the processes determining oral absorption. A sensitivity analysis was performed using a PBPK model describing phenytoin to determine a solubility requirement for phenytoin salts needed to achieve optimal oral bioavailability for a given dose. Based on the analysis, it is predicted that phenytoin salts with solubility greater than 0.3 mg/mL would show no further increases in oral bioavailability. A salt screen was performed using a variety of phenytoin salts. The piperazine and sodium salts showed the lowest and highest aqueous solubility and were tested in vivo. Consistent with our analysis, we observed no significant differences in oral bioavailability for these two salts despite an approximate 60 fold difference in solubility. Our study illustrates that higher solubility salts sometimes provide no additional improvements in oral bioavailability and PBPK modeling can be utilized as an important tool to provide guidance to the salt selection and define a salt solubility requirement.