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

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, th...

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Bibliographic Details
Published inAdvanced drug delivery reviews Vol. 64; pp. 4 - 17
Main Authors Lipinski, Christopher A., Lombardo, Franco, Dominy, Beryl W., Feeney, Paul J.
Format Journal Article
LanguageEnglish
Published Kidlington Elsevier B.V 01.12.2012
Elsevier
Subjects
Biological and medical sciences
Computational alert
General pharmacology
H-Bond donors and acceptors
Medical sciences
MLogP
MWT
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Poor absorption or permeation
Rule of 5
Solubility calculation
Thermodynamic solubility
Turbidimetric solubility
Computational alert
Rule of 5
Thermodynamic solubility
MLogP
Poor absorption or permeation
H-Bond donors and acceptors
MWT
Solubility calculation
Turbidimetric solubility
Drug
Pharmaceutical technology
Permeation
Solubility
Permeability
Research and development
Thermodynamics
Absorption
Pharmacokinetics
Physicochemical properties
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Summary: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.
ISSN:0169-409X
1872-8294
DOI:10.1016/j.addr.2012.09.019