Details

Autor(en) / Beteiligte

• Lipinski, Christopher A
• Lombardo, Franco
• Dominy, Beryl W
• Feeney, Paul J

Titel

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

Ist Teil von

• Advanced drug delivery reviews, 2001-03, Vol.46 (1), p.3-26

Ort / Verlag

Shannon: Elsevier B.V

Erscheinungsjahr

2001

Quelle

Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)

Beschreibungen/Notizen

• Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting `the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS 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 and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.