The DOI matches its Crossref record; 49 of the 51 references it cites were found in a registry or an index.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1
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 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.
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In the citing paper
“which typically results in low aqueous solubility and high metabolic clearance (Lipinski et al., 2001).”
From A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance (2016) · cites this paper as Lipinski et al., 2001
In the citing paper
“Considering the restrictive Lipinski’s rules for BBB penetration (MW ≤ 450, clogP ≤5, hydrogen bond donors ≤ 5, hydrogen bond acceptors ≤ 10, polar surface area ≤ 90 Å2) and the calculated logBB values (Table S2), both L1 and L2 satisfy these requirements, suggesting that these compounds should be capable of crossing the BBB.”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [75]
In the citing paper
“In general, PROTAC physicochemical property space falls beyond the ‘rule of 5’ (refs59,60) owing to the bifunctional nature of the molecules.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [59]
Citations
Cites
Solvents and Solvent Effects in Organic Chemistry
Reichardt, C. L. (2002) · Wiley eBooks · doi:10.1002/3527601791 · Cited by 5,795
Abraham, M. H. (1993) · Chemical Society Reviews · doi:10.1039/cs9932200073 · Cited by 1,968
Are Crystal Structures Predictable?
Gavezzotti, A. (1994) · Accounts of Chemical Research · doi:10.1021/ar00046a004 · Cited by 922
The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography
Abraham, M. H., & McGowan, J. C. (1987) · Chromatographia · doi:10.1007/bf02311772 · Cited by 861
Abraham, M. H., Chadha, H. S., Whiting, G. S., & Mitchell, R. C. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830806 · Cited by 766
Calculating log Poct from structures
Leo, A. J. (1993) · Chemical Reviews · doi:10.1021/cr00020a001 · Cited by 705
Solubility and partitioning I: Solubility of nonelectrolytes in water
Yalkowsky, S. H., & Valvani, S. C. (1980) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600690814 · Cited by 581
Functional group contributions to drug-receptor interactions
Andrews, P. R., Craik, D. J., & Martin, J. L. (1984) · Journal of Medicinal Chemistry · doi:10.1021/jm00378a021 · Cited by 538
Simple Method of Calculating Octanol/Water Partition Coefficient.
MORIGUCHI, I., Hirono, S., Qian, L. I. U., Nakagome, I., & MATSUSHITA, Y. (1992) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.40.127 · Cited by 536
Abraham, M. H. (1993) · Journal of Physical Organic Chemistry · doi:10.1002/poc.610061204 · Cited by 354
Research works printed but not linked: 3
- Lipinski, C.A. (1995) Computational alerts for potential absorption problems: profiles of clinically tested drugs. In: Tools for Oral Absorption. Part Two. Predicting Human Absorption. BIOTEC, PDD symposium, AAPS, Miami.
- Workshop on Oral Drug Delivery: Interface Between Discovery and Development. Report and Recommendations. National Institutes of Health, National Institute of General Medical Sciences. Herndon, Virginia, December 5–7, 1993.
- Lipinski, C.A., Davis, A.L., Aldridge, P.K. and Brown, C.W. (1994) Biologically relevant UV-based solubility assays. Pharmaceutical Analysis Session, 45th Pittsburgh Conf., Chicago, Oral Presentation 959.
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Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Daina, A., Michielin, O., & Zoete, V. (2017) · Scientific Reports · doi:10.1038/srep42717 · Cited by 18,367
Lead- and drug-like compounds: the rule-of-five revolution
Lipinski, C. A. (2004) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2004.11.007 · Cited by 6,455
Self-citationPires, D. E. V., Blundell, T. L., & Ascher, D. B. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00104 · Cited by 6,126
TCMSP: a database of systems pharmacology for drug discovery from herbal medicines
Ru, J., Li, P., Wang, J., Zhou, W., Li, B., Huang, C., Li, P., Guo, Z., Tao, W., Yang, Y., et al. (2014) · Journal of Cheminformatics · doi:10.1186/1758-2946-6-13 · Cited by 5,092
Metadata
- Authors
- Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Lipinski, Christopher A
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2001-03
- Volume
- 46
- Issue
- 1-3
- Pages
- 3-26
- ISSN
- 0169-409X (ISSN-L)
- OpenAlex
- W2135732933
- Cited by
- 18,139
- References
- 51
- Citations by year
- 2026: 869 · 2025: 962 · 2024: 1264 · 2023: 1296 · 2022: 1248 · 2021: 1459 · 2020: 1317 · 2019: 945 · 2018: 876 · 2017: 791 · 2016: 790 · 2015: 724 · 2014: 752 · 2013: 741 · 2012: 708
- FWCI
- 19.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Materials Science › Materials Chemistry › Crystallization and Solubility Studies
- Keywords
- drug solubility, intestinal permeability, Rule of 5, molecular weight, lipophilicity, polymorphism, linear free energy relationships, thermodynamic solubility, solubility prediction, drug absorption
- MeSH terms
- Adsorption, Chemistry, Physical, Computers, Pharmaceutical Preparations, Permeability, Pharmacology, Solubility, Thermodynamics, Chemical Phenomena
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