Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

Experimental and computational approaches to estimate solubility and permea bility in discovery and development settings are described. In the discover y setting 'the rule of 5' predicts that poor absorption or permeation is mo re likely when there are more than 5 H-bond donors, 10 H-bond accepters, th e molecular weight (MWT) is greater than 500 and the calculated Log P (CLog P) is greater than 5 (or MlogP>4.15). Computational methodology for the rul e-based Morigucki Log P (MLogP) calculation is described. Turbidimetric sol ubility measurement is described and applied to known drugs. High throughpu t screening (HTS) leads tend to have higher MWT and Log P and lower turbidi metric solubility than leads in the pre-MTS era. In the development setting , solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships a nd Log P approaches are critically reviewed. Useful predictions are possibl e in closely related analog series when coupled with experimental thermodyn amic solubility measurements. (C) 2001 Elsevier Science B.V. All rights res erved.