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The rule of 5 was designed to estimate the likelihood of poor absorption or permeation, noting the impact of poor solubility. This Perspective explores the impact of various physicochemical descriptors and contemporary lipophilicity measurements on permeability and solubility, showing that the distribution coefficient log D7.4 (rather than log P) is the most impactful parameter. Molecular weight, almost invariably the defining characteristic of "beyond the rule of 5" compounds, has little impact on solubility when log D7.4 measurements
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