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| Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings |
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| Author(s): Lipinski CA, Lombardo F, Dominy BW, Feeney PJ |
| Source: ADVANCED DRUG DELIVERY REVIEWS Volume: 46 Issue: 1-3 Pages: 3-26 Published: MAR 1 2001 |
| Times Cited: 866 References: 49 |
| Abstract: 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 accepters, 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 Morigucki 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-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 and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements. (C) 2001 Elsevier Science B.V. All rights reserved. |
| Document Type: Review |
| Language: English |
| Reprint Address: Lipinski, CA (reprint author), Pfizer Inc, Div Cent Res, Groton, CT 06340 USA |
Addresses:
1. Pfizer Inc, Div Cent Res, Groton, CT 06340 USA |
| Publisher: ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS |
| Subject Category: Pharmacology & Pharmacy |
| IDS Number: 413KJ |
| ISSN: 0169-409X |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |